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http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0002-24.2024?rss=1
GPR4 is a proton-sensing G-protein-coupled receptor implicated in many peripheral and central physiological processes. GPR4 expression has previously been assessed only via detection of the cognate transcript or indirectly, by use of fluorescent reporters. In this work, CRISPR/Cas9 knock-in technology was used to encode a hemagglutinin (HA) epitope tag within the endogenous locus of Gpr4 and visualize GPR4-HA in the mouse central nervous system using a specific, well-characterized HA antibody; GPR4 expression was further verified by complementary Gpr4 mRNA detection. HA immunoreactivity was found in a limited set of brain regions, including in the retrotrapezoid nucleus (RTN), serotonergic raphe nuclei, medial habenula, lateral septum, and several thalamic nuclei. GPR4 expression was not restricted to cells of a specific neurochemical identity as it was observed in excitatory, inhibitory, and aminergic neuronal cell groups. HA immunoreactivity was not detected in brain vascular endothelium, despite clear expression of Gpr4 mRNA in endothelial cells. In the RTN, GPR4 expression was detected at the soma and in proximal dendrites along blood vessels and the ventral surface of the brainstem; HA immunoreactivity was not detected in RTN projections to two known target regions. This localization of GPR4 protein in mouse brain neurons corroborates putative sites of expression where its function has been previously implicated (e.g., CO2-regulated breathing by RTN) and provides a guide for where GPR4 could contribute to other CO2/H+ modulated brain functions. Finally, GPR4-HA animals provide a useful reagent for further study of GPR4 in other physiological processes outside of the brain.
]]>2024-03-11T09:30:27-07:00info:doi/10.1523/ENEURO.0002-24.2024hwp:master-id:eneuro;ENEURO.0002-24.2024Society for Neuroscience2024-03-11Integrative Systems113ENEURO.0002-24.2024ENEURO.0002-24.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0020-24.2024?rss=1
Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and motion direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute patients (<3 months post-V1 stroke) and 12 chronic patients (>6 months post-V1 stroke) were pretested and then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts as their performance improved. At baseline, more subacute than chronic participants could correctly discriminate the orientation of high-contrast Gabors in their blind field, but all failed to perform this task at lower contrasts, even when 10 Hz flicker or motion direction were added. Training improved CS in a greater portion of subacute than that of chronic participants, but no one attained normal CS, even when stimuli contained flicker or motion. We conclude that, unlike the near-complete training-induced restoration of high-contrast visual discrimination abilities, V1 damage in adulthood may severely limit the residual visual system's ability to regain normal CS. Our results support the notion that CS involves different neural substrates and computations than those required for orientation and direction discrimination in V1-damaged visual systems.
]]>2024-03-14T09:30:31-07:00info:doi/10.1523/ENEURO.0020-24.2024hwp:master-id:eneuro;ENEURO.0020-24.2024Society for Neuroscience2024-03-14Disorders of the Nervous System113ENEURO.0020-24.2024ENEURO.0020-24.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0024-23.2024?rss=1
Parkinson's disease (PD) patients harbor seeding-competent α-synuclein (α-syn) in their cerebrospinal fluid (CSF), which is mainly produced by the choroid plexus (ChP). Nonetheless, little is known about the role of the CSF and the ChP in PD pathogenesis. To address this question, we used an intracerebroventricular (icv) injection mouse model to assess CSF α-syn spreading and its short- and long-term consequences on the brain. Hereby, we made use of seeding-competent, recombinant α-syn preformed fibrils (PFF) that are known to induce aggregation and subsequent spreading of endogenous α-syn in stereotactic tissue injection models. Here, we show that icv-injected PFF, but not monomers (Mono), are rapidly removed from the CSF by interaction with the ChP. Additionally, shortly after icv injection both Mono and PFF were detected in the olfactory bulb and striatum. This spreading was associated with increased inflammation and complement activation in these tissues as well as leakage of the blood–CSF barrier. Despite these effects, a single icv injection of PFF didn't induce a decline in motor function. In contrast, daily icv injections over the course of 5 days resulted in deteriorated grip strength and formation of phosphorylated α-syn inclusions in the brain 2 months later, whereas dopaminergic neuron levels were not affected. These results point toward an important clearance function of the CSF and the ChP, which could mediate removal of PFF from the brain, whereby chronic exposure to PFF in the CSF may negatively impact blood–CSF barrier functionality and PD pathology.
]]>2024-03-08T09:30:27-08:00info:doi/10.1523/ENEURO.0024-23.2024hwp:master-id:eneuro;ENEURO.0024-23.2024Society for Neuroscience2024-03-08Disorders of the Nervous System113ENEURO.0024-23.2024ENEURO.0024-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0027-23.2024?rss=1
The neural mechanisms underlying the exogenous coding and neural entrainment to repetitive auditory stimuli have seen a recent surge of interest. However, few studies have characterized how parametric changes in stimulus presentation alter entrained responses. We examined the degree to which the brain entrains to repeated speech (i.e., /ba/) and nonspeech (i.e., click) sounds using phase-locking value (PLV) analysis applied to multichannel human electroencephalogram (EEG) data. Passive cortico-acoustic tracking was investigated in N = 24 normal young adults utilizing EEG source analyses that isolated neural activity stemming from both auditory temporal cortices. We parametrically manipulated the rate and periodicity of repetitive, continuous speech and click stimuli to investigate how speed and jitter in ongoing sound streams affect oscillatory entrainment. Neuronal synchronization to speech was enhanced at 4.5 Hz (the putative universal rate of speech) and showed a differential pattern to that of clicks, particularly at higher rates. PLV to speech decreased with increasing jitter but remained superior to clicks. Surprisingly, PLV entrainment to clicks was invariant to periodicity manipulations. Our findings provide evidence that the brain's neural entrainment to complex sounds is enhanced and more sensitized when processing speech-like stimuli, even at the syllable level, relative to nonspeech sounds. The fact that this specialization is apparent even under passive listening suggests a priority of the auditory system for synchronizing to behaviorally relevant signals.
]]>2024-03-04T09:30:22-08:00info:doi/10.1523/ENEURO.0027-23.2024hwp:master-id:eneuro;ENEURO.0027-23.2024Society for Neuroscience2024-03-04Sensory and Motor Systems113ENEURO.0027-23.2024ENEURO.0027-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0048-24.2024?rss=1
2024-03-14T09:30:31-07:00info:doi/10.1523/ENEURO.0048-24.2024hwp:resource-id:eneuro;11/3/ENEURO.0048-24.2024Society for Neuroscience2024-03-14Editorial113ENEURO.0048-24.2024ENEURO.0048-24.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0082-24.2024?rss=1
2024-03-14T09:30:31-07:00info:doi/10.1523/ENEURO.0082-24.2024hwp:resource-id:eneuro;11/3/ENEURO.0082-24.2024Society for Neuroscience2024-03-14Editorial113ENEURO.0082-24.2024ENEURO.0082-24.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0113-24.2024?rss=1
2024-03-28T09:30:42-07:00info:doi/10.1523/ENEURO.0113-24.2024hwp:resource-id:eneuro;11/3/ENEURO.0113-24.2024Society for Neuroscience2024-03-28Editorial113ENEURO.0113-24.2024ENEURO.0113-24.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0120-23.2024?rss=1
Daylight vision is mediated by cone photoreceptors in vertebrates, which synapse with bipolar cells (BCs) and horizontal (HCs) cells. This cone synapse is functionally and anatomically complex, connecting to eight types of depolarizing BCs (DBCs) and five types of hyperpolarizing BCs (HBCs) in mice. The dendrites of DBCs and HCs cells make invaginating ribbon synapses with the cone axon terminal, while HBCs form flat synapses with the cone pedicles. The molecular architecture that underpins this organization is relatively poorly understood. To identify new proteins involved in synapse formation and function we used an unbiased proteomic approach and identified LRFN2 (leucine-rich repeat and fibronectin III domain-containing 2) as a component of the DBC signaling complex. LRFN2 is selectively expressed at cone terminals and colocalizes with PNA, and other DBC signalplex members. In LRFN2 deficient mice, the synaptic markers: LRIT3, ELFN2, mGluR6, TRPM1 and GPR179 are properly localized. Similarly, LRFN2 expression and localization is not dependent on these synaptic proteins. In the absence of LRFN2 the cone-mediated photopic electroretinogram b-wave amplitude is reduced at the brightest flash intensities. These data demonstrate that LRFN2 absence compromises normal synaptic transmission between cones and cone DBCs.
]]>2024-03-21T09:30:33-07:00info:doi/10.1523/ENEURO.0120-23.2024hwp:master-id:eneuro;ENEURO.0120-23.2024Society for Neuroscience2024-03-21Neuronal Excitability113ENEURO.0120-23.2024ENEURO.0120-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0175-23.2024?rss=1
Alzheimer's disease (AD) is associated with brain accumulation of synaptotoxic amyloid-β (Aβ) peptides produced by the proteolytic processing of amyloid precursor protein (APP). Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. In rodents, soluble Aβ oligomers (Aβo) impair hippocampus-dependent learning and memory, promote dendritic spine loss, inhibit NMDA-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP), and promote synaptic depression (LTD), at least in part through activation of the Ca2+-CaM-dependent phosphatase calcineurin (CaN). Yet, questions remain regarding Aβ-dependent postsynaptic CaN signaling specifically at the synapse to mediate its synaptotoxicity. Here, we use pharmacologic and genetic approaches to demonstrate a role for postsynaptic signaling via A kinase-anchoring protein 150 (AKAP150)-scaffolded CaN in mediating Aβ-induced dendritic spine loss in hippocampal neurons from rats and mice of both sexes. In particular, we found that Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs), which were previously shown to signal through AKAP-anchored CaN to promote both LTD and Aβ-dependent inhibition of LTP, are also required upstream of AKAP-CaN signaling to mediate spine loss via overexpression of APP containing multiple mutations linked to familial early-onset AD (FAD) and increased Aβ production. In addition, we found that the CaN-dependent nuclear factor of activated T-cells (NFAT) transcription factors is required downstream to promote Aβ-mediated dendritic spine loss. Finally, we identified the E3-ubiquitin ligase Mdm2, which was previously linked to LTD and developmental synapse elimination, as a downstream NFAT target gene upregulated by Aβ whose enzymatic activity is required for Aβ-mediated spine loss.
]]>2024-03-08T09:30:27-08:00info:doi/10.1523/ENEURO.0175-23.2024hwp:master-id:eneuro;ENEURO.0175-23.2024Society for Neuroscience2024-03-08Disorders of the Nervous System113ENEURO.0175-23.2024ENEURO.0175-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0192-23.2023?rss=1
Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer’s disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2–3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11–20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC FosB, a transcription factor that increases after 1–2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.
]]>2024-03-04T09:30:22-08:00info:doi/10.1523/ENEURO.0192-23.2023hwp:master-id:eneuro;ENEURO.0192-23.2023Society for Neuroscience2024-03-04Disorders of the Nervous System113ENEURO.0192-23.2023ENEURO.0192-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0241-23.2024?rss=1
The internal globus pallidus (GPi) is a major source of tonic GABAergic inhibition to the motor thalamus. In parkinsonism, the firing rate of GPi neurons is increased, and their pattern switches from a tonic to a burst mode, two pathophysiological changes associated with increased GABAergic pallidothalamic activity. In this study, we used high-resolution 3D electron microscopy to demonstrate that GPi terminals in the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM), the two main GPi-recipient motor thalamic nuclei in monkeys, undergo significant morphometric changes in parkinsonian monkeys including (1) increased terminal volume in both nuclei; (2) increased surface area of synapses in both nuclei; (3) increased number of synapses/GPi terminals in the CM, but not VApc; and (4) increased total volume, but not number, of mitochondria/terminals in both nuclei. In contrast to GPi terminals, the ultrastructure of putative GABAergic nonpallidal terminals was not affected. Our results also revealed striking morphological differences in terminal volume, number/area of synapses, and volume/number of mitochondria between GPi terminals in VApc and CM of control monkeys. In conclusion, GABAergic pallidothalamic terminals are endowed with a high level of structural plasticity that may contribute to the development and maintenance of the abnormal increase in pallidal GABAergic outflow to the thalamus in the parkinsonian state. Furthermore, the evidence for ultrastructural differences between GPi terminals in VApc and CM suggests that morphologically distinct pallidothalamic terminals from single pallidal neurons may underlie specific physiological properties of pallidal inputs to VApc and CM in normal and diseased states.
]]>2024-03-21T09:30:33-07:00info:doi/10.1523/ENEURO.0241-23.2024hwp:resource-id:eneuro;11/3/ENEURO.0241-23.2024Society for Neuroscience2024-03-21Disorders of the Nervous System113ENEURO.0241-23.2024ENEURO.0241-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0246-23.2024?rss=1
The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during postnatal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between four youth (age 16–22) and four middle-aged adults (age 44–53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons, and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of oligodendrocyte progenitors and microglia decreased in middle-age, indicating that the cellular composition of human SEZ is remodeled between youth and adulthood. The expression of genes related to nervous system development was higher across different cell types, including NSCs, in youth as compared with middle-age. These transcriptional changes suggest ongoing central nervous system plasticity in the SEZ in youth, which declined in middle-age.
]]>2024-03-04T09:30:22-08:00info:doi/10.1523/ENEURO.0246-23.2024hwp:master-id:eneuro;ENEURO.0246-23.2024Society for Neuroscience2024-03-04Development113ENEURO.0246-23.2024ENEURO.0246-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0259-23.2024?rss=1
Nonoscillatory measures of brain activity such as the spectral slope and Lempel–Ziv complexity are affected by many neurological disorders and modulated by sleep. A multitude of frequency ranges, particularly a broadband (encompassing the full spectrum) and a narrowband approach, have been used especially for estimating the spectral slope. However, the effects of choosing different frequency ranges have not yet been explored in detail. Here, we evaluated the impact of sleep stage and task engagement (resting, attention, and memory) on slope and complexity in a narrowband (30–45 Hz) and broadband (1–45 Hz) frequency range in 28 healthy male human subjects (21.54 ± 1.90 years) using a within-subject design over 2 weeks with three recording nights and days per subject. We strived to determine how different brain states and frequency ranges affect slope and complexity and how the two measures perform in comparison. In the broadband range, the slope steepened, and complexity decreased continuously from wakefulness to N3 sleep. REM sleep, however, was best discriminated by the narrowband slope. Importantly, slope and complexity also differed between tasks during wakefulness. While narrowband complexity decreased with task engagement, the slope flattened in both frequency ranges. Interestingly, only the narrowband slope was positively correlated with task performance. Our results show that slope and complexity are sensitive indices of brain state variations during wakefulness and sleep. However, the spectral slope yields more information and could be used for a greater variety of research questions than Lempel–Ziv complexity, especially when a narrowband frequency range is used.
]]>2024-03-28T09:30:42-07:00info:doi/10.1523/ENEURO.0259-23.2024hwp:master-id:eneuro;ENEURO.0259-23.2024Society for Neuroscience2024-03-28Cognition and Behavior113ENEURO.0259-23.2024ENEURO.0259-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0268-23.2023?rss=1
In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit.
]]>2024-03-04T09:30:22-08:00info:doi/10.1523/ENEURO.0268-23.2023hwp:master-id:eneuro;ENEURO.0268-23.2023Society for Neuroscience2024-03-04Disorders of the Nervous System113ENEURO.0268-23.2023ENEURO.0268-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0272-23.2024?rss=1
Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions and even causes mental dysfunctions such as depression and anxiety disorders. In this article, we conducted a multimodal study cross-sectionally and longitudinally, to evaluate how neuropathic pain affects the brain. Using the spared nerve injury (SNI) model which promotes long-lasting mechanical allodynia, results showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 2 weeks after injury. There are significant changes in the activity of the left thalamus (Th_L) and left olfactory bulb (OB_L) brain regions after SNI, as evidenced by both the blood oxygen level-dependent (BOLD) signal and c-Fos expression. Importantly, these changes were closely related to mechanical pain behavior of rats. However, it is worth noting that after morphine administration for analgesia, only the increased activity in the TH region is reversed, while the decreased activity in the OB region becomes more prominent. Functional connectivity (FC) and c-Fos correlation analysis further showed these two regions of interest (ROIs) exhibit different FC patterns with other brain regions. Our study comprehensively revealed the adaptive changes of brain neural networks induced by nerve injury in both cross-sectional and longitudinal dimensions and emphasized the abnormal activity and FC of Th_L and OB_L in the pathological condition. It provides reliable assistance in exploring the intricate mechanisms of diseases.
]]>2024-03-08T09:30:27-08:00info:doi/10.1523/ENEURO.0272-23.2024hwp:master-id:eneuro;ENEURO.0272-23.2024Society for Neuroscience2024-03-08Sensory and Motor Systems113ENEURO.0272-23.2024ENEURO.0272-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0277-23.2023?rss=1
The temporal dynamics within the semantic brain network and its dependence on stimulus and task parameters are still not well understood. Here, we addressed this by decoding task as well as stimulus information from source-estimated EEG/MEG human data. We presented the same visual word stimuli in a lexical decision (LD) and three semantic decision (SD) tasks. The meanings of the presented words varied across five semantic categories. Source space decoding was applied over time in five ROIs in the left hemisphere (anterior and posterior temporal lobe, inferior frontal gyrus, primary visual areas, and angular gyrus) and one in the right hemisphere (anterior temporal lobe). Task decoding produced sustained significant effects in all ROIs from 50 to 100 ms, both when categorizing tasks with different semantic demands (LD-SD) as well as for similar semantic tasks (SD-SD). In contrast, a semantic word category could only be decoded in lATL, rATL, PTC, and IFG, between 250 and 500 ms. Furthermore, we compared two approaches to source space decoding: conventional ROI-by-ROI decoding and combined-ROI decoding with back-projected activation patterns. The former produced more reliable results for word category decoding while the latter was more informative for task decoding. This indicates that task effects are distributed across the whole semantic network while stimulus effects are more focal. Our results demonstrate that the semantic network is widely distributed but that bilateral anterior temporal lobes together with control regions are particularly relevant for the processing of semantic information.
]]>2024-03-04T09:30:22-08:00info:doi/10.1523/ENEURO.0277-23.2023hwp:master-id:eneuro;ENEURO.0277-23.2023Society for Neuroscience2024-03-04Cognition and Behavior113ENEURO.0277-23.2023ENEURO.0277-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0283-23.2024?rss=1
The type I transmembrane protein BT-IgSF is predominantly localized in the brain and testes. It belongs to the coxsackievirus and adenovirus receptor subgroup of Ig cell adhesion proteins, which are hypothesized to regulate connexin expression or localization. Here, we studied the putative link between BT-IgSF and connexins in astrocytes, ependymal cells, and neurons of the mouse. Global knock-out of BT-IgSF caused an increase in the clustering of connexin43 (Gja1), but not of connexin30 (Gjb6), on astrocytes and ependymal cells. Additionally, knock-out animals displayed reduced expression levels of connexin43 protein in the cortex and hippocampus. Importantly, analysis of biocytin spread in hippocampal or cortical slices from mature mice of either sex revealed a decrease in astrocytic cell–cell coupling in the absence of BT-IgSF. Blocking either protein biosynthesis or proteolysis showed that the lysosomal pathway increased connexin43 degradation in astrocytes. Localization of connexin43 in subcellular compartments was not impaired in astrocytes of BT-IgSF mutants. In contrast to connexin43, the localization and expression of connexin36 (Gjd2) on neurons were not affected by the absence of BT-IgSF. Overall, our data indicate that the IgCAM BT-IgSF is essential for correct gap junction–mediated astrocyte–astrocyte cell communication.
]]>2024-03-21T09:30:33-07:00info:doi/10.1523/ENEURO.0283-23.2024hwp:master-id:eneuro;ENEURO.0283-23.2024Society for Neuroscience2024-03-21Development113ENEURO.0283-23.2024ENEURO.0283-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0284-23.2023?rss=1
The preBötzinger complex (preBötC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBötC to perform several in silico experiments exploring how differences in network topology and the intrinsic properties of preBötC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBötC networks in silico exhibit variable responses to simulated opioids, similar to the preBötC network in vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBötC network that may regulate its susceptibility to opioids.
]]>2024-03-07T09:30:21-08:00info:doi/10.1523/ENEURO.0284-23.2023hwp:master-id:eneuro;ENEURO.0284-23.2023Society for Neuroscience2024-03-07Sensory and Motor Systems113ENEURO.0284-23.2023ENEURO.0284-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0296-23.2024?rss=1
Spontaneous eye blinking is gaining popularity as a proxy for higher cognitive functions, as it is readily modulated by both environmental demands and internal processes. Prior studies were impoverished in sample size, sex representation, and age distribution, making it difficult to establish a complete picture of the behavior. Here we present eye-tracking data from a large cohort of normative participants (n = 604; 393 F; aged 5–93 years) performing two tasks: one with structured, discrete trials (interleaved pro-/anti-saccade task, IPAST) and one with a less structured, continuous organization in which participants watch movies (free-viewing; FV). Sex- and age-based analyses revealed that females had higher blink rates between the ages of 22 and 58 years in the IPAST and 22 and 34 years in FV. We derived a continuous measure of blink probability to reveal behavioral changes driven by stimulus appearance in both paradigms. In the IPAST, blinks were suppressed near stimulus appearance, particularly on correct anti-saccade trials, which we attribute to the stronger inhibitory control required for anti-saccades compared with pro-saccades. In FV, blink suppression occurred immediately after scene changes, and the effect was sustained on scenes where gaze clustered among participants (indicating engagement of attention). Females were more likely than males to blink during appearance of novel stimuli in both tasks, but only within the age bin of 18–44 years. The consistency of blink patterns in each paradigm endorses blinking as a sensitive index for changes in visual processing and attention, while sex and age differences drive interindividual variability.
]]>2024-03-05T09:30:23-08:00info:doi/10.1523/ENEURO.0296-23.2024hwp:master-id:eneuro;ENEURO.0296-23.2024Society for Neuroscience2024-03-05Sensory and Motor Systems113ENEURO.0296-23.2024ENEURO.0296-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0305-23.2023?rss=1
Currently there are numerous methods to evaluate peripheral nerve stimulation interfaces in rats, with stimulation-evoked ankle torque being one of the most prominent. Commercial rat ankle torque measurement systems and custom one-off solutions have been published in the literature. However, commercial systems are proprietary and costly and do not allow for customization. One-off lab-built systems have required specialized machining expertise, and building plans have previously not been made easily accessible. Here, detailed building plans are provided for a low-cost, open-source, and basic ankle torque measurement system from which additional customization can be made. A hindlimb stabilization apparatus was developed to secure and stabilize a rat's hindlimb, while allowing for simultaneous ankle-isometric torque and lower limb muscle electromyography (EMG). The design was composed mainly of adjustable 3D-printed components to accommodate anatomical differences between rat hindlimbs. Additionally, construction and calibration procedures of the rat hindlimb stabilization apparatus were demonstrated in this study. In vivo torque measurements were reliably acquired and corresponded to increasing stimulation amplitudes. Furthermore, implanted leads used for intramuscular EMG recordings complemented torque measurements and were used as an additional functional measurement in evaluating the performance of a peripheral nerve stimulation interface. In conclusion, an open-source and noninvasive platform, made primarily with 3D-printed components, was constructed for reliable data acquisition of evoked motor activity in rat models. The purpose of this apparatus is to provide researchers a versatile system with adjustable components that can be tailored to meet user-defined experimental requirements when evaluating motor function of the rat hindlimbs.
]]>2024-03-06T09:30:21-08:00info:doi/10.1523/ENEURO.0305-23.2023hwp:master-id:eneuro;ENEURO.0305-23.2023Society for Neuroscience2024-03-06Novel Tools and Methods113ENEURO.0305-23.2023ENEURO.0305-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0337-23.2023?rss=1
Neural dedifferentiation, the finding that neural representations tend to be less distinct in older adults compared with younger adults, has been associated with age-related declines in memory performance. Most studies assessing the relation between memory and neural dedifferentiation have evaluated how age impacts the distinctiveness of neural representations for different visual categories (e.g., scenes and objects). However, how age impacts the quality of neural representations at the level of individual items is still an open question. Here, we present data from an age-comparative fMRI study that aimed to understand how the distinctiveness of neural representations for individual stimuli differs between younger and older adults and relates to memory outcomes. Pattern similarity searchlight analyses yielded indicators of neural dedifferentiation at the level of individual items as well as at the category level in posterior occipital cortices. We asked whether age differences in neural distinctiveness at each representational level were associated with inter- and/or intraindividual variability in memory performance. While age-related dedifferentiation at both the item and category level related to between-person differences in memory, neural distinctiveness at the category level also tracked within-person variability in memory performance. Concurrently, neural distinctiveness at the item level was strongly associated with neural distinctiveness at the category level both within and across participants, elucidating a potential representational mechanism linking item- and category-level distinctiveness. In sum, we provide evidence that age-related neural dedifferentiation co-exists across multiple representational levels and is related to memory performance.
]]>2024-03-22T09:30:34-07:00info:doi/10.1523/ENEURO.0337-23.2023hwp:master-id:eneuro;ENEURO.0337-23.2023Society for Neuroscience2024-03-22Cognition and Behavior113ENEURO.0337-23.2023ENEURO.0337-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0344-23.2023?rss=1
Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting gamma-aminobutyric acid type A receptors (GABAARs) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that gamma-aminobutyric acid type A receptors containing the α1 subunit (α1GABAARs) are primarily located in the synapse, whereas gamma-aminobutyric acid type A receptors containing the α5 subunit (α5GABAARs) are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected an siRNA into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, the knockdown of radixin significantly decreased radixin-associated α5GABAARs and increased the proportion of synaptic α5GABAARs, without changing the overall expression of α5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic α5GABAARs; thus, efficacy may be diminished in conditions where aberrant hippocampal activity is present.
]]>2024-03-27T09:30:39-07:00info:doi/10.1523/ENEURO.0344-23.2023hwp:master-id:eneuro;ENEURO.0344-23.2023Society for Neuroscience2024-03-27Disorders of the Nervous System113ENEURO.0344-23.2023ENEURO.0344-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0364-23.2024?rss=1
First-order thalamic nuclei receive feedforward signals from peripheral receptors and relay these signals to primary sensory cortex. Primary sensory cortex, in turn, provides reciprocal feedback to first-order thalamus. Because the vast majority of sensory thalamocortical inputs target primary sensory cortex, their complementary corticothalamic neurons are assumed to be similarly restricted to primary sensory cortex. We upend this assumption by characterizing morphologically diverse neurons in multiple mid-level visual cortical areas of the primate (Macaca mulatta) brain that provide direct feedback to the primary visual thalamus, the dorsal lateral geniculate nucleus (LGN). Although the majority of geniculocortical neurons project to primary visual cortex (V1), a minority, located mainly in the koniocellular LGN layers, provide direct input to extrastriate visual cortex. These "V1-bypassing" projections may be implicated in blindsight. We hypothesized that geniculocortical inputs directly targeting extrastriate cortex should be complemented by reciprocal corticogeniculate circuits. Using virus-mediated circuit tracing, we discovered corticogeniculate neurons throughout three mid-level extrastriate areas: MT, MST, and V4. Quantitative morphological analyses revealed nonuniform distributions of unique cell types across areas. Many extrastriate corticogeniculate neurons had spiny stellate morphology, suggesting possible targeting of koniocellular LGN layers. Importantly though, multiple morphological types were observed across areas. Such morphological diversity could suggest parallel streams of V1-bypassing corticogeniculate feedback at multiple stages of the visual processing hierarchy. Furthermore, the presence of corticogeniculate neurons across visual cortex necessitates a reevaluation of the LGN as a hub for visual information rather than a simple relay.
]]>2024-03-15T09:30:42-07:00info:doi/10.1523/ENEURO.0364-23.2024hwp:master-id:eneuro;ENEURO.0364-23.2024Society for Neuroscience2024-03-15Sensory and Motor Systems113ENEURO.0364-23.2024ENEURO.0364-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0369-23.2024?rss=1
Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior.
]]>2024-03-05T09:30:23-08:00info:doi/10.1523/ENEURO.0369-23.2024hwp:master-id:eneuro;ENEURO.0369-23.2024Society for Neuroscience2024-03-05Integrative Systems113ENEURO.0369-23.2024ENEURO.0369-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0373-23.2024?rss=1
Rodent models, such as mice and rats, are commonly used to examine retinal ganglion cell damage in eye diseases. However, as nocturnal animals, rodent retinal structures differ from primates, imposing significant limitations in studying retinal pathology. Tree shrews (Tupaia belangeri) are small, diurnal paraprimates that exhibit superior visual acuity and color vision compared with mice. Like humans, tree shrews have a dense retinal nerve fiber layer (RNFL) and a thick ganglion cell layer (GCL), making them a valuable model for investigating optic neuropathies. In this study, we applied high-resolution visible-light optical coherence tomography to characterize the tree shrew retinal structure in vivo and compare it with that of humans and mice. We quantitatively characterize the tree shrew's retinal layer structure in vivo, specifically examining the sublayer structures within the inner plexiform layer (IPL) for the first time. Next, we conducted a comparative analysis of retinal layer structures among tree shrews, mice, and humans. We then validated our in vivo findings in the tree shrew inner retina using ex vivo confocal microscopy. The in vivo and ex vivo analyses of the shrew retina build the foundation for future work to accurately track and quantify the retinal structural changes in the IPL, GCL, and RNFL during the development and progression of human optic diseases.
]]>2024-03-27T09:30:39-07:00info:doi/10.1523/ENEURO.0373-23.2024hwp:master-id:eneuro;ENEURO.0373-23.2024Society for Neuroscience2024-03-27Novel Tools and Methods113ENEURO.0373-23.2024ENEURO.0373-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0383-23.2024?rss=1
When learning a new motor skill, people often must use trial and error to discover which movement is best. In the reinforcement learning framework, this concept is known as exploration and has been linked to increased movement variability in motor tasks. For locomotor tasks, however, increased variability decreases upright stability. As such, exploration during gait may jeopardize balance and safety, making reinforcement learning less effective. Therefore, we set out to determine if humans could acquire and retain a novel locomotor pattern using reinforcement learning alone. Young healthy male and female participants walked on a treadmill and were provided with binary reward feedback (indicated by a green checkmark on the screen) that was tied to a fixed monetary bonus, to learn a novel stepping pattern. We also recruited a comparison group who walked with the same novel stepping pattern but did so by correcting for target error, induced by providing real-time veridical visual feedback of steps and a target. In two experiments, we compared learning, motor variability, and two forms of motor memories between the groups. We found that individuals in the binary reward group did, in fact, acquire the new walking pattern by exploring (increasing motor variability). Additionally, while reinforcement learning did not increase implicit motor memories, it resulted in more accurate explicit motor memories compared with the target error group. Overall, these results demonstrate that humans can acquire new walking patterns with reinforcement learning and retain much of the learning over 24 h.
]]>2024-03-15T09:30:42-07:00info:doi/10.1523/ENEURO.0383-23.2024hwp:master-id:eneuro;ENEURO.0383-23.2024Society for Neuroscience2024-03-15Cognition and Behavior113ENEURO.0383-23.2024ENEURO.0383-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0385-23.2024?rss=1
Problematic alcohol consumption is associated with deficits in decision-making and alterations in prefrontal cortex neural activity likely contribute. We hypothesized that the differences in cognitive control would be evident between male Wistars and a model of genetic risk: alcohol-preferring P rats. Cognitive control is split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus, whereas reactive control elicits goal-directed behavior at the time of a stimulus. We hypothesized that Wistars would show proactive control over alcohol seeking whereas P rats would show reactive control over alcohol seeking. Neural activity was recorded from the prefrontal cortex during an alcohol seeking task with two session types. On congruent sessions, the conditioned stimulus (CS+) was on the same side as alcohol access. Incongruent sessions presented alcohol opposite the CS+. Wistars, but not P rats, made more incorrect approaches during incongruent sessions, suggesting that Wistars utilized the previously learned rule. This motivated the hypothesis that neural activity reflecting proactive control would be observable in Wistars but not P rats. While P rats showed differences in neural activity at times of alcohol access, Wistars showed differences prior to approaching the sipper. These results support our hypothesis that Wistars are more likely to engage in proactive cognitive control strategies whereas P rats are more likely to engage in reactive cognitive control strategies. Although P rats were bred to prefer alcohol, the differences in cognitive control may reflect a sequela of behaviors that mirror those in humans at risk for an AUD.
]]>2024-03-27T09:30:39-07:00info:doi/10.1523/ENEURO.0385-23.2024hwp:master-id:eneuro;ENEURO.0385-23.2024Society for Neuroscience2024-03-27Disorders of the Nervous System113ENEURO.0385-23.2024ENEURO.0385-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0393-23.2024?rss=1
The control of ingestive behavior is complex and involves input from many different sources, including the gustatory system. Signals transmitted via the taste nerves trigger responses that promote or discourage ingestion. The lingual taste nerves innervate 70% of taste buds, yet their role in the control of food selection and intake remarkably remains relatively underinvestigated. Here we used our custom five-item Food Choice Monitor to compare postsurgical behavioral responses to chow and a five-choice cafeteria diet (CAF) between male rats that had sham surgery (SHAM) or histologically verified transection of the chorda tympani and glossopharyngeal nerves (2NX). Compared with SHAM rats, 2NX rats ate significantly more of the high-fat CAF foods. The altered food choices led to dramatically increased fat intake and substantially reduced carbohydrate intake by 2NX vs SHAM rats. Furthermore, whether offered chow or CAF, 2NX rats ate fewer, larger meals each day. Eating rates implied that, compared with SHAM, 2NX rats were equally motivated to consume CAF but less motivated to eat chow. Even with these differences, energy intake and weight gain trajectories remained similar between SHAM and 2NX rats. Although some rats experienced CAF before surgery, contrary to our expectations, the effects of prior CAF experience on postsurgical eating were minimal. In conclusion, although total energy intake was unaffected, our results clearly indicate that information from one or both lingual taste nerves has a critical role in food selection, regulation of macronutrient intake, and meal termination but not long-term energy balance.
]]>2024-03-07T09:30:21-08:00info:doi/10.1523/ENEURO.0393-23.2024hwp:master-id:eneuro;ENEURO.0393-23.2024Society for Neuroscience2024-03-07Sensory and Motor Systems113ENEURO.0393-23.2024ENEURO.0393-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0399-23.2024?rss=1
Synchronization in the gamma band (25–150 Hz) is mediated by PV+ inhibitory interneurons, and evidence is accumulating for the essential role of gamma oscillations in cognition. Oscillations can arise in inhibitory networks via synaptic interactions between individual oscillatory neurons (mean-driven) or via strong recurrent inhibition that destabilizes the stationary background firing rate in the fluctuation-driven balanced state, causing an oscillation in the population firing rate. Previous theoretical work focused on model neurons with Hodgkin's Type 1 excitability (integrators) connected by current-based synapses. Here we show that networks comprised of simple Type 2 oscillators (resonators) exhibit a supercritical Hopf bifurcation between synchrony and asynchrony and a gradual transition via cycle skipping from coupled oscillators to stochastic population oscillator (SPO), as previously shown for Type 1. We extended our analysis to homogeneous networks with conductance rather than current based synapses and found that networks with hyperpolarizing inhibitory synapses were more robust to noise than those with shunting synapses, both in the coupled oscillator and SPO regime. Assuming that reversal potentials are uniformly distributed between shunting and hyperpolarized values, as observed in one experimental study, converting synapses to purely hyperpolarizing favored synchrony in all cases, whereas conversion to purely shunting synapses made synchrony less robust except at very high conductance strengths. In mature neurons the synaptic reversal potential is controlled by chloride cotransporters that control the intracellular concentrations of chloride and bicarbonate ions, suggesting these transporters as a potential therapeutic target to enhance gamma synchrony and cognition.
]]>2024-03-27T09:30:39-07:00info:doi/10.1523/ENEURO.0399-23.2024hwp:master-id:eneuro;ENEURO.0399-23.2024Society for Neuroscience2024-03-27Neuronal Excitability113ENEURO.0399-23.2024ENEURO.0399-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0410-23.2024?rss=1
Touch sensation from the glabrous skin of the hand is essential for precisely controlling dexterous movements, yet the neural mechanisms by which tactile inputs influence motor circuits remain largely unexplored. By pairing air-puff tactile stimulation on the hand's glabrous skin with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), we examined the effects of tactile stimuli from single or multiple fingers on corticospinal excitability and M1's intracortical circuits. Our results showed that when we targeted the hand's first dorsal interosseous (FDI) muscle with TMS, homotopic (index finger) tactile stimulation, regardless of its point (fingertip or base), reduced corticospinal excitability. Conversely, heterotopic (ring finger) tactile stimulation had no such effect. Notably, stimulating all five fingers simultaneously led to a more pronounced decrease in corticospinal excitability than stimulating individual fingers. Furthermore, tactile stimulation significantly increased intracortical facilitation (ICF) and decreased long-interval intracortical inhibition (LICI) but did not affect short-interval intracortical inhibition (SICI). Considering the significant role of the primary somatosensory cortex (S1) in tactile processing, we also examined the effects of downregulating S1 excitability via continuous theta burst stimulation (cTBS) on tactile–motor interactions. Following cTBS, the inhibitory influence of tactile inputs on corticospinal excitability was diminished. Our findings highlight the spatial specificity of tactile inputs in influencing corticospinal excitability. Moreover, we suggest that tactile inputs distinctly modulate M1's excitatory and inhibitory pathways, with S1 being crucial in facilitating tactile–motor integration.
]]>2024-03-05T09:30:23-08:00info:doi/10.1523/ENEURO.0410-23.2024hwp:resource-id:eneuro;11/3/ENEURO.0410-23.2024Society for Neuroscience2024-03-05Sensory and Motor Systems113ENEURO.0410-23.2024ENEURO.0410-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0416-23.2024?rss=1
The transition from acute to chronic pain involves maladaptive plasticity in central nociceptive pathways. Growing evidence suggests that changes within the parabrachial nucleus (PBN), an important component of the spino–parabrachio–amygdaloid pain pathway, are key contributors to the development and maintenance of chronic pain. In animal models of chronic pain, PBN neurons become sensitive to normally innocuous stimuli and responses to noxious stimuli become amplified and more often produce afterdischarges that outlast the stimulus. Using ex vivo slice electrophysiology and two mouse models of neuropathic pain, sciatic cuff and chronic constriction of the infraorbital nerve (CCI-ION), we find that changes in the firing properties of PBN neurons and a shift in inhibitory synaptic transmission may underlie this phenomenon. Compared to PBN neurons from shams, a larger proportion of PBN neurons from mice with a sciatic cuff were spontaneously active at rest, and these same neurons showed increased excitability relative to shams. In contrast, quiescent PBN neurons from cuff mice were less excitable than those from shams. Despite an increase in excitability in a subset of PBN neurons, the presence of afterdischarges frequently observed in vivo were largely absent ex vivo in both injury models. However, GABAB-mediated presynaptic inhibition of GABAergic terminals is enhanced in PBN neurons after CCI-ION. These data suggest that the amplified activity of PBN neurons observed in rodent models of chronic pain arise through a combination of changes in firing properties and network excitability.
]]>2024-03-07T09:30:21-08:00info:doi/10.1523/ENEURO.0416-23.2024hwp:master-id:eneuro;ENEURO.0416-23.2024Society for Neuroscience2024-03-07Neuronal Excitability113ENEURO.0416-23.2024ENEURO.0416-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0418-23.2023?rss=1
Aging comes with declines in episodic memory. Memory decline is accompanied by structural and functional alterations within key brain regions, including the hippocampus and lateral prefrontal cortex, as well as their affiliated default and frontoparietal control networks. Most studies have examined how structural or functional differences relate to memory independently. Here we implemented a multimodal, multivariate approach to investigate how interactions between individual differences in structural integrity and functional connectivity relate to episodic memory performance in healthy aging. In a sample of younger (N = 111; mean age, 22.11 years) and older (N = 78; mean age, 67.29 years) adults, we analyzed structural MRI and multiecho resting-state fMRI data. Participants completed measures of list recall (free recall of words from a list), associative memory (cued recall of paired words), and source memory (cued recall of the trial type, or the sensory modality in which a word was presented). The findings revealed that greater structural integrity of the posterior hippocampus and middle frontal gyrus were linked with a pattern of increased within-network connectivity, which together were related to better associative and source memory in older adulthood. Critically, older adults displayed better memory performance in the context of decreased hippocampal volumes when structural differences were accompanied by functional reorganization. This functional reorganization was characterized by a pruning of connections between the hippocampus and the limbic and frontoparietal control networks. Our work provides insight into the neural mechanisms that underlie age-related compensation, revealing that the functional architecture associated with better memory performance in healthy aging is tied to the structural integrity of the hippocampus and prefrontal cortex.
]]>2024-03-27T09:30:39-07:00info:doi/10.1523/ENEURO.0418-23.2023hwp:master-id:eneuro;ENEURO.0418-23.2023Society for Neuroscience2024-03-27Cognition and Behavior113ENEURO.0418-23.2023ENEURO.0418-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0423-23.2024?rss=1
Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.
]]>2024-03-22T09:30:34-07:00info:doi/10.1523/ENEURO.0423-23.2024hwp:master-id:eneuro;ENEURO.0423-23.2024Society for Neuroscience2024-03-22Sensory and Motor Systems113ENEURO.0423-23.2024ENEURO.0423-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0433-23.2023?rss=1
Sleep and muscle injury-related pain are in negative relationship, and sleep extension may be a favorable countermeasure. In response to muscle injury, an adaptive sleep response has been described in rats, characterized by an increase in total sleep time (TST) and nonrapid eye movement (NREM) sleep. This study examined the effects of photoperiod lengthening (a model of sleep prolongation in rats) on the sleep characteristics of muscle-injured rats and whether this lengthening could benefit injury-induced mechanical hyperalgesia using the Von Frey test. Switching from the conventional 12:12 light/dark (LD) photoperiod (light on: 08:00–20:00) to LD 16:8 (light extended to 24:00) gives rats an extra window of sleep. Our results show higher TST and NREM sleep times in LD 16:8 versus LD 12:12 injured rats during 4 h of light lengthening for 7 d postinjury, showing the efficiency of photoperiod lengthening to increase sleep time in injured rats. In addition, a cumulative effect with the adaptive sleep response to muscle injury occurred with higher TST and NREM sleep times in LD 16:8 injured versus noninjured rats during the dark period, reflecting the high need for sleep after the injury. Greater stability and higher relative delta power of NREM sleep during the extended light period were also observed in injured rats. Finally, the extended photoperiod limits the muscle injury-induced mechanical hyperalgesia for 13 d and allows faster recovery of the baseline mechanical threshold. This is associated with reduced pro-inflammatory cytokines levels in the hippocampus, a brain structure involved in pain processing.
]]>2024-03-07T09:30:21-08:00info:doi/10.1523/ENEURO.0433-23.2023hwp:master-id:eneuro;ENEURO.0433-23.2023Society for Neuroscience2024-03-07Cognition and Behavior113ENEURO.0433-23.2023ENEURO.0433-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0445-23.2024?rss=1
The cortical visual area, V4, has been considered to code contours that contribute to the intermediate-level representation of objects. The neural responses to the complex contour features intrinsic to natural contours are expected to clarify the essence of the representation. To approach the cortical coding of natural contours, we investigated the simultaneous coding of multiple contour features in monkey (Macaca fuscata) V4 neurons and their population-level representation. A substantial number of neurons showed significant tuning for two or more features such as curvature and closure, indicating that a substantial number of V4 neurons simultaneously code multiple contour features. A large portion of the neurons responded vigorously to acutely curved contours that surrounded the center of classical receptive field, suggesting that V4 neurons tend to code prominent features of object contours. The analysis of mutual information (MI) between the neural responses and each contour feature showed that most neurons exhibited similar magnitudes for each type of MI, indicating that many neurons showing the responses depended on multiple contour features. We next examined the population-level representation by using multidimensional scaling analysis. The neural preferences to the multiple contour features and that to natural stimuli compared with silhouette stimuli increased along with the primary and secondary axes, respectively, indicating the contribution of the multiple contour features and surface textures in the population responses. Our analyses suggested that V4 neurons simultaneously code multiple contour features in natural images and represent contour and surface properties in population.
]]>2024-03-15T09:30:42-07:00info:doi/10.1523/ENEURO.0445-23.2024hwp:master-id:eneuro;ENEURO.0445-23.2024Society for Neuroscience2024-03-15Sensory and Motor Systems113ENEURO.0445-23.2024ENEURO.0445-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0478-23.2024?rss=1
Neuroprotection after injury or in neurodegenerative disease remains a major goal for basic and translational neuroscience. Retinal ganglion cells (RGCs), the projection neurons of the eye, degenerate in optic neuropathies after axon injury, and there are no clinical therapies to prevent their loss or restore their connectivity to targets in the brain. Here we demonstrate a profound neuroprotective effect of the exogenous expression of various Ca2+/calmodulin-dependent protein kinase II (CaMKII) isoforms in mice. A dramatic increase in RGC survival following the optic nerve trauma was elicited by the expression of constitutively active variants of multiple CaMKII isoforms in RGCs using adeno-associated viral (AAV) vectors across a 100-fold range of AAV dosing in vivo. Despite this neuroprotection, however, short-distance RGC axon sprouting was suppressed by CaMKII, and long-distance axon regeneration elicited by several pro-axon growth treatments was likewise inhibited even as CaMKII further enhanced RGC survival. Notably, in a dose-escalation study, AAV-expressed CaMKII was more potent for axon growth suppression than the promotion of survival. That diffuse overexpression of constitutively active CaMKII strongly promotes RGC survival after axon injury may be clinically valuable for neuroprotection per se. However, the associated strong suppression of the optic nerve axon regeneration demonstrates the need for understanding the intracellular domain- and target-specific CaMKII activities to the development of CaMKII signaling pathway-directed strategies for the treatment of optic neuropathies.
]]>2024-03-28T09:30:42-07:00info:doi/10.1523/ENEURO.0478-23.2024hwp:resource-id:eneuro;11/3/ENEURO.0478-23.2024Society for Neuroscience2024-03-28Disorders of the Nervous System113ENEURO.0478-23.2024ENEURO.0478-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0490-23.2023?rss=1
The motor cortex comprises the primary descending circuits for flexible control of voluntary movements and is critically involved in motor skill learning. Motor skill learning is impaired in patients with Parkinson's disease, but the precise mechanisms of motor control and skill learning are still not well understood. Here we have used transgenic mice, electrophysiology, in situ hybridization, and neural tract-tracing methods to target genetically defined cell types expressing D1 and D2 dopamine receptors in the motor cortex. We observed that putative D1 and D2 dopamine receptor-expressing neurons (D1+ and D2+, respectively) are organized in highly segregated, nonoverlapping populations. Moreover, based on ex vivo patch-clamp recordings, we showed that D1+ and D2+ cells have distinct morphological and electrophysiological properties. Finally, we observed that chemogenetic inhibition of D2+, but not D1+, neurons disrupts skilled forelimb reaching in adult mice. Overall, these results demonstrate that dopamine receptor-expressing cells in the motor cortex are highly segregated and play a specialized role in manual dexterity.
]]>2024-03-26T09:30:46-07:00info:doi/10.1523/ENEURO.0490-23.2023hwp:master-id:eneuro;ENEURO.0490-23.2023Society for Neuroscience2024-03-26Sensory and Motor Systems113ENEURO.0490-23.2023ENEURO.0490-23.2023
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0497-23.2024?rss=1
Synaptic plasticity is important for learning and memory formation; it describes the strengthening or weakening of connections between synapses. The postsynaptic part of excitatory synapses resides in dendritic spines, which are small protrusions on the dendrites. One of the key features of synaptic plasticity is its correlation with the size of these spines. A long-lasting synaptic strength increase [long-term potentiation (LTP)] is only possible through the reconfiguration of the actin spine cytoskeleton. Here, we develop an experimentally informed three-dimensional computational model in a moving boundary framework to investigate this reconfiguration. Our model describes the reactions between actin and actin-binding proteins leading to the cytoskeleton remodeling and their effect on the spine membrane shape to examine the spine enlargement upon LTP. Moreover, we find that the incorporation of perisynaptic elements enhances spine enlargement upon LTP, exhibiting the importance of accounting for these elements when studying structural LTP. Our model shows adaptation to repeated stimuli resulting from the interactions between spine proteins and mechanical forces.
]]>2024-03-11T09:30:27-07:00info:doi/10.1523/ENEURO.0497-23.2024hwp:master-id:eneuro;ENEURO.0497-23.2024Society for Neuroscience2024-03-11Neuronal Excitability113ENEURO.0497-23.2024ENEURO.0497-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0500-23.2024?rss=1
In the field of behavioral neuroscience, the classification and scoring of animal behavior play pivotal roles in the quantification and interpretation of complex behaviors displayed by animals. Traditional methods have relied on video examination by investigators, which is labor-intensive and susceptible to bias. To address these challenges, research efforts have focused on computational methods and image-processing algorithms for automated behavioral classification. Two primary approaches have emerged: marker- and markerless-based tracking systems. In this study, we showcase the utility of "Augmented Reality University of Cordoba" (ArUco) markers as a marker-based tracking approach for assessing rat engagement during a nose-poking go/no-go behavioral task. In addition, we introduce a two-state engagement model based on ArUco marker tracking data that can be analyzed with a rectangular kernel convolution to identify critical transition points between states of engagement and distraction. In this study, we hypothesized that ArUco markers could be utilized to accurately estimate animal engagement in a nose-poking go/no-go behavioral task, enabling the computation of optimal task durations for behavioral testing. Here, we present the performance of our ArUco tracking program, demonstrating a classification accuracy of 98% that was validated against the manual curation of video data. Furthermore, our convolution analysis revealed that, on average, our animals became disengaged with the behavioral task at ~75 min, providing a quantitative basis for limiting experimental session durations. Overall, our approach offers a scalable, efficient, and accessible solution for automated scoring of rodent engagement during behavioral data collection.
]]>2024-03-05T09:30:23-08:00info:doi/10.1523/ENEURO.0500-23.2024hwp:master-id:eneuro;ENEURO.0500-23.2024Society for Neuroscience2024-03-05Novel Tools and Methods113ENEURO.0500-23.2024ENEURO.0500-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0501-23.2024?rss=1
Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine release, and the degree of this increase is highly dependent on firing frequency. The superlinearity and frequency dependence of dopamine release implicate short-term plasticity processes. The presynaptic Ca2+-sensor synaptotagmin-7 (SYT7) has suitable properties to mediate such short-term plasticity and has been implicated in regulating dopamine release from somatodendritic compartments. Here, we use a genetically encoded dopamine sensor and whole-cell electrophysiology in Syt7 KO mice to determine how SYT7 contributes to both axonal and somatodendritic dopamine release. We find that SYT7 mediates a hidden component of facilitation of release from dopamine terminals that can be unmasked by lowering initial release probability or by predepressing synapses with low-frequency stimulation. Depletion of SYT7 increased short-term depression and reduced release during stimulations that mimic in vivo firing. Recordings of D2-mediated inhibitory postsynaptic currents in the substantia nigra pars compacta (SNc) confirmed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of dopamine release, which may explain the frequency dependence of dopamine signaling seen in vivo.
]]>2024-03-12T09:30:30-07:00info:doi/10.1523/ENEURO.0501-23.2024hwp:master-id:eneuro;ENEURO.0501-23.2024Society for Neuroscience2024-03-12Neuronal Excitability113ENEURO.0501-23.2024ENEURO.0501-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0518-22.2024?rss=1
Layer 4 of the rodent somatosensory cortex has unitary structures called barrels that receive tactile information from individual vibrissae. Barrels in the anterolateral barrel subfield (ALBSF) are much smaller and have gained less attention than larger barrels in the posteromedial barrel subfield (PMBSF), though the former outnumber the latter. We compared the morphological features of barrels between the ALBSF and PMBSF in male mice using deformation-free tangential sections and confocal optical slice-based, precise reconstructions of barrels. The average volume of a single barrel in the ALBSF was 34.7% of that in the PMBSF, but the numerical density of parvalbumin (PV)-positive interneurons in the former was 1.49 times higher than that in the latter. Moreover, PV neuron density in septa was 2.08 times higher in the ALBSF than that in the PMBSF. The proportions of PV neuron number to both all neuron number and all GABAergic neuron number in the ALBSF were also higher than those in the PMBSF. Somata of PV neurons in barrels and septa in the ALBSF received 1.64 and 1.50 times more vesicular glutamate transporter Type 2–labeled boutons than those in the PMBSF, suggesting more potent feedforward inhibitory circuits in the ALBSF. The mode of connectivity through dendritic gap junctions among PV neurons also differed between the ALBSF and PMBSF. Clusters of smaller unitary structures containing a higher density of representative GABAergic interneurons with differential morphological features in the ALBSF suggest a division of functional roles in the two vibrissa–barrel systems, as has been demonstrated by behavioral studies.
]]>2024-03-26T09:30:46-07:00info:doi/10.1523/ENEURO.0518-22.2024hwp:master-id:eneuro;ENEURO.0518-22.2024Society for Neuroscience2024-03-26Sensory and Motor Systems113ENEURO.0518-22.2024ENEURO.0518-22.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0519-23.2024?rss=1
Keeping track of multiple visually identical and independently moving objects is a remarkable feature of the human visual system. Theoretical accounts for this ability focus on resource-based models that describe parametric decreases of performance with increasing demands during the task (i.e., more relevant items, closer distances, higher speed). Additionally, the presence of two central tracking resources, one within each hemisphere, has been proposed, allowing for an independent maintenance of moving targets within each visual hemifield. Behavioral evidence in favor of such a model shows that human subjects are able to track almost twice as many targets across both hemifields compared with within one hemifield. A number of recent publications argue for two separate and parallel tracking mechanisms during standard object tracking tasks that allow for the maintenance of the relevant information in a location-based and object-based manner. Unique electrophysiological correlates for each of those processes have been identified. The current study shows that these electrophysiological components are differentially present during tracking within either the left or right hemifield. The present results suggest that targets are mostly maintained as an object-based representation during left hemifield tracking, while location-based resources are preferentially engaged during right hemifield tracking. Interestingly, the manner of representation does not seem to have an impact on behavioral performance within the subjects, while the electrophysiological component indicating object-based tracking does correlate with performance between subjects. We propose that hemifield independence during multiple-object tracking may be an indication of the underlying hemispheric bias for parallel location-based and object-based tracking mechanisms.
]]>2024-03-26T09:30:46-07:00info:doi/10.1523/ENEURO.0519-23.2024hwp:master-id:eneuro;ENEURO.0519-23.2024Society for Neuroscience2024-03-26Cognition and Behavior113ENEURO.0519-23.2024ENEURO.0519-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0531-23.2024?rss=1
Fueled by the recent and controversial brain-wide association studies in humans, the animal neuroimaging community has also begun questioning whether using larger sample sizes is necessary for ethical and effective scientific progress. In this opinion piece, we illustrate two opposing views on sample size extremes in MRI-based animal neuroimaging.
]]>2024-03-18T09:30:28-07:00info:doi/10.1523/ENEURO.0531-23.2024hwp:resource-id:eneuro;11/3/ENEURO.0531-23.2024Society for Neuroscience2024-03-18Novel Tools and Methods113ENEURO.0531-23.2024ENEURO.0531-23.2024
http://www.eneuro.org/cgi/content/short/11/3/ENEURO.0541-23.2024?rss=1
Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.
]]>2024-03-25T09:30:38-07:00info:doi/10.1523/ENEURO.0541-23.2024hwp:master-id:eneuro;ENEURO.0541-23.2024Society for Neuroscience2024-03-25Cognition and Behavior113ENEURO.0541-23.2024ENEURO.0541-23.2024