Elsevier

Behavioural Brain Research

Volume 353, 1 November 2018, Pages 168-175
Behavioural Brain Research

Effect of electrical stimulation of the infralimbic and prelimbic cortices on anxiolytic-like behavior of rats during the elevated plus-maze test, with particular reference to multiunit recording of the behavior-associated neural activity

https://doi.org/10.1016/j.bbr.2018.07.005Get rights and content

Highlights

  • The infralimbic cortex (IL) regulates anxiety-like behavior in rats.

  • IL stimulation increases open arm entries in the elevated plus-maze.

  • Prelimbic cortex stimulation does not induce significant behavioral changes.

  • Multiunit activity of the IL increases prior to entry from closed to open arms.

  • The IL may be involved in overcoming anxiety-like behavior in rats.

Abstract

Fear and anxiety affect the activities of daily living and require concerted management, such as coping strategies, to preserve quality of life. The infralimbic (IL) and prelimbic (PL) medial prefrontal cortices have been implicated in the regulation of fear- and anxiety-like behavior, but their roles in overcoming fear- and anxiety-like behavior remain unknown. We investigated the anxiolytic-like effects of electrical stimulation of the IL and PL cortices in rats during the elevated plus-maze test. IL stimulation led to a significantly higher percentage of time spent and entries in the open arms, whereas PL stimulation did not have any significant behavioral effects. Subsequently, we recorded multiunit activity from the IL and PL cortices in rats using a wireless telemetry device, to determine whether activation of the IL occurs when rats enter the open arms in the elevated plus-maze test. The firing rate of IL neurons increased 1–3 s prior to entry from the closed arm to the open arm, whereas there were no corresponding changes in the firing rate of PL neurons. Taken together, the present findings suggest that the IL plays a key role in exerting active action to overcome anxiety-like behavior.

Introduction

Fear and anxiety often disturb the activities of daily living and sometimes require concerted coping strategies to preserve the quality of life. Although the amygdala has been identified as an important brain region in emotional processing [[1], [2], [3], [4]], playing a role in the expression of fear and anxiety [[5], [6], [7], [8], [9]], the neural mechanisms underlying the process of overcoming fear and anxiety remain unclear. The medial prefrontal cortex (mPFC) has direct projections to the amygdala and is thought to regulate its activity [10]. Lesion or inactivation of the mPFC modify fear- and anxiety-like behavioral responses in rodents; however, the nature of this effect is somewhat controversial. For example, Jinks and McGregor [11] reported that lesion of the mPFC inhibits coping behavior in rats exposed to the threating or aversive environment in the elevated plus-maze test; similarly, Lisboa et al. [12] showed that pharmacological inactivation of the mPFC enhances anxiety-like behavior in rats submitted to the elevated plus-maze. In contrast, Shar and Treit [13,14] reported that lesion and pharmacological inactivation of the mPFC produces anxiolytic-like effects in the elevated plus-maze test. Hamani et al. [15] demonstrated that electrical activation of the mPFC induces antidepressant-like effects in the forced swimming test, while Scopinho et al. [16] found that pharmacological inactivation of the mPFC induces an antidepressant-like effect in this paradigm. Although these reports are not in agreement, they suggest that the mPFC functions as the neural basis for the control of fear and anxiety.

The mPFC is a heterogeneous structure. The ventral mPFC includes the infralimbic cortex (IL) and prelimbic cortex (PL), which have different projections to the amygdala. Whereas IL fibers project to widespread areas of the amygdala, PL fibers primarily project to the central and basolateral nuclei [10]. Electrophysiological studies of fear conditioning have shown that increased firing of IL neurons correlates with the recall of extinction learning, whereas increased firing of PL neurons correlates with sustained fear [[17], [18], [19]]. A study using intracortical stimulation similarly showed that IL stimulation decreases freezing behavior in response to a conditioned tone, whereas PL stimulation increases freezing behavior [20]. These studies of fear conditioning suggest that the IL and PL exert distinct functions with regard to fear and anxiety.

The purpose of the present study was to determine the roles of the IL and PL in anxiolytic-like behavioral effects. We investigated behavioral responses to electrical stimulation of the IL and PL and the neural activity of the respective neurons in rats during the elevated plus-maze test. We hypothesized that activation of the IL is associated with anxiolytic-like responses, whereas the activation of the PL is associated with anxiety-like responses.

Section snippets

Subjects

We used a total of 136 male Sprague-Dawley rats (Japan SLC, Inc., Shizuoka, Japan) that were 9–12 weeks of age at the time of testing: 77 rats were used to investigate behavioral responses to electrical stimulation of the IL and PL, and 59 rats were used to examine the neural activity of IL and PL neurons in the elevated plus-maze test. They were group-housed in a room with controlled temperature (24 °C) on a reverse 12-h light/dark cycle (lights on at 20:00 h) with food and water available ad

Histology

The tip positions of the stimulating electrodes in experiment 1 and the recording electrodes in experiment 2 were examined in coronal sections. The borders between the IL and PL were delimited based on the cytoarchitectonic features described by Krettek and Price [30]: the IL was characterized by relatively indistinct lamination and an uneven border between layer I and layer II, whereas the PL was characterized by a well-defined lamination, in which layer V contained large dark stained cells

Discussion

The present study demonstrated that IL stimulation induces a significant increase in the percentage of time spent and entries in the open arms of the elevated plus-maze compared to PL stimulation or no stimulation. In some cases, the stimulation applied to the ventral PL also increased the percentage of time spent and entries in the open arms. Several studies have reported that the dorsal and ventral portions of the PL show different connectivity [[31], [32], [33], [34]], distribution of

Conclusions

Our study showed that IL stimulation exerts anxiolytic-like effects, evidenced by a higher percentage of time spent and entries in the open arms of the maze; this was not observed during PL stimulation or no stimulation. Multiunit activity recordings from the IL and PL indicated an increased firing rate of IL neurons 1–3 s prior to entries from a closed to an open arm, whereas no significant changes were observed for PL neurons. These findings suggest that the IL plays a key role in exerting

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS) to A.M. (KAKENHI 17H02121) and a Grant-in-Aid for JSPS Fellows to T.S. (267534). The authors thank Mei Ito and Saki Ito for their excellent assistance with animal experiments.

References (60)

  • A. Bahi

    Sustained lentiviral-mediated overexpression of microRNA124a in the dentate gyrus exacerbates anxiety- and autism-like behaviors associated with neonatal isolation in rats

    Behav. Brain Res.

    (2016)
  • A. Adhikari et al.

    Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity

    Neuron

    (2011)
  • H.W. Berendse et al.

    Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat

    Neuroscience

    (1991)
  • G. Hedou et al.

    Expression of sensitization to amphetamine and dynamics of dopamine neurotransmission in different laminae of the rat medial prefrontal cortex

    Neuropharmacology

    (2001)
  • H. Ahmadi et al.

    Involvement of the nucleus accumbens shell dopaminergic system in prelimbic NMDA-induced anxiolytic-like behaviors

    Neuropharmacology

    (2013)
  • C.A.J. Stern et al.

    Activity in prelimbic cortex is required for adjusting the anxiety response level during the elevated plus-maze retest

    Neuroscience

    (2010)
  • C. Hamani et al.

    Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats

    J. Psychiatr. Res.

    (2010)
  • A.A. Wilber et al.

    Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction

    Neuroscience

    (2011)
  • J.D. Bremner et al.

    Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study

    Biol. Psychiatry

    (1999)
  • M. Casarrubea et al.

    Temporal structure of the rat’s behavior in elevated plus maze test

    Behav. Brain Res.

    (2013)
  • P.M. Wall et al.

    Differential effects of infralimbic vs. ventromedial orbital PFC lidocaine infusions in CD-1 mice on defensive responding in the mouse defense test battery and rat exposure test

    Brain Res.

    (2004)
  • L. Weiskrantz

    Behavioral changes associated with ablation of the amygdaloid complex in monkeys

    J. Comp. Physiol. Psychol.

    (1956)
  • J. LeDoux

    The emotional brain, fear, and the amygdala

    Cell Mol. Neurobiol.

    (2003)
  • D. Paré et al.

    New vistas on amygdala networks in conditioned fear

    J. Neurophysiol.

    (2004)
  • K.M. Tye et al.

    Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning

    Nature

    (2008)
  • N.H. Kalin et al.

    The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate

    J. Neurosci.

    (2004)
  • H.M.B. Lesscher et al.

    Amygdala protein kinase C epsilon regulates corticotropin-releasing factor and anxiety-like behavior

    Genes Brain Behav.

    (2008)
  • A. Etkin et al.

    Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder

    Arch. Gen. Psychiatry

    (2009)
  • B. Roozendaal et al.

    Stress, memory and the amygdala

    Nat. Rev. Neurosci.

    (2009)
  • R.P. Vertes

    Differential projections of the infralimbic and prelimbic cortex in the rat

    Synapse

    (2004)
  • Cited by (14)

    • 2-Heptanone reduces inhibitory control of the amygdala over the prelimbic region in rats

      2021, Neuroscience Letters
      Citation Excerpt :

      Prelimbic cortex activity is considered to be at the basis of the expression of innate fear behavior [40]. In the presence of a predator, neuronal activity increases in amygdala and mPFC regions, and greater neuronal activity in these mPFC regions is related to low anxiety indicators [1], mainly in the IL [4,36]. In the present study, the paucisynaptic response was followed by a relatively long-lasting period of a lower firing rate, and then neuronal activity surpassed the basal level, likely representing a compensatory response that leads to a complex behavioral response.

    • Endocannabinoids, cannabinoids and the regulation of anxiety

      2021, Neuropharmacology
      Citation Excerpt :

      In contrast, the infralimbic cortex promotes resilience to stress-induced anxiety by encoding perception of behavioural control (Christianson et al., 2009) and safety (Milad et al., 2007; Sangha et al., 2014). More specifically, stimulation of the infralimbic cortex reduces anxiety-like behaviour in the EPM (Shimizu et al, 2018). This regulation occurs through top-down control of limbic circuits involved in the generation of emotional states, such as the amygdala (Motzkin et al., 2015).

    • Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

      2021, Acta Pharmaceutica Sinica B
      Citation Excerpt :

      The elevated plus maze (DB015, Zhishu Duobao Biotechnology Co., Ltd.,) can evaluate the anxiety state of the animals. On the Day 9 after administration, the mice were placed at the central area of the elevated plus maze, and the software recorded the time and movement videos automatically within 5 min44. The freezing behavior test is performed in a conditional fear box (Shanghai Jiliang Software Technology Co., Ltd.).

    • Responsivity of lateral septum-mPFC connections in alloxan-induced hyperglycemia

      2019, Behavioural Brain Research
      Citation Excerpt :

      The meaning of an increase in inhibitory responsivity of LSN-PL and LSN-IL connections may be revealed by the following observations. Activation studies have shown that although electrical stimulation of the PL produces some similar actions, stimulation of the IL produces an increase in the number of entries into the open arms of the elevated plus maze, and multiple-unit activity in the IL indicates an increase in firing rate in the IL before entries into the open arm [59]. Fear conditioning with footshock stress produces a short increase in neuronal firing in the PL, followed by recovery.

    View all citing articles on Scopus
    View full text