Invited reviewAmygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors
Introduction
The amygdala, located within the medial temporal lobe, is divided into at least 13 distinct subnuclei; the most clearly defined being the basolateral amygdala (BLA), the lateral amygdala (LA), and the central amygdala (CeA) (Amaral and Price, 1984, Amunts et al., 2005). The CeA connects the amygdala proper with the extended amygdala, located between the amygdala and the nucleus accumbens (NAc). The extended amygdala is comprised of the bed nucleus of the stria terminalis (BNST) as well as other interconnected nuclei such as the dorsal substantia innominata (Cassell et al., 1999) (Table 1).
Primary functions of the amygdala include emotional learning and regulation (Phelps and LeDoux, 2005), memory formation (Packard and Cahill, 2001), and reward processing (Baxter and Murray, 2002). The BNST is made up of a vast array of cell types including GABAergic and glutamatergic efferent populations, as well as GABAergic and cholinergic interneurons (Ju and Swanson, 1989, Ju et al., 1989). Overlapping with these populations are cells expressing an assortment of neuropeptides including NPY, CRF, enkephalin, dynorphin, and substance P (Kozicz et al., 1997). The BNST is involved in sustained fear behaviors (Walker and Davis, 2008, Walker et al., 2009), anxiety-like behaviors (Walker and Davis, 1997, 2008; Cecchi et al., 2002), and stress induced reinstatement of drug seeking (Erb et al., 2000, Erb et al., 2001a, Erb et al., 2001b, Wang et al., 2001).
Human neuroimaging studies have provided strong evidence for the role of the amygdala and extended amygdala structures in drug and alcohol addiction. A meta-analysis of data collected from fMRI and PET studies revealed that the amygdala and nucleus accumbens (NAc), an area that receives dense innervation from the amygdala, show the most robust neural activation in response to drug-associated cues (Chase et al., 2011). Additionally, two functional fMRI studies found correlations between NAc activity and drug cravings (Kufahl et al., 2005, Risinger et al., 2005). Changes in the amygdala have also been associated with alcohol use disorders. An MRI study found that the amygdala is smaller in children of parents with alcohol use disorders (Hill et al., 2001). Furthermore, gray matter is decreased in the medial prefrontal cortex (mPFC), a region that receives strong innervation from the amygdala, in patients with alcohol use disorders (Pfefferbaum et al., 1998).
In this review we outline amygdala and BNST afferent and efferent connectivity, as well as animal studies that have implicated these circuits in the development and maintenance of drug addiction.
Section snippets
Role of BLA in addiction
The amygdala is thought to be necessary for attributing emotional value to cues that predict salient events. The BLA, in particular, has an integral role in processing affective states (Phelps and LeDoux, 2005). Importantly, the BLA has been implicated as a critical modulator of reinstatement of drug seeking in rodents (Fuchs et al., 2005). Lesions of the BLA disrupt cue-induced reinstatement of cocaine self-administration (Meil and See, 1997), conditioned reinforcement for a natural reward (
BLA afferents
The BLA receives strong innervation from the thalamus, hippocampus, and medial prefrontal cortex (Fig. 1A) (Ottersen, 1982, Albanese and Minciacchi, 1983, van Vulpen et al., 1989). The BLA also receives dopaminergic innervation from the ventral tegmental area (VTA, Fig. 1A) (Albanese and Minciacchi, 1983), and this circuit may underlie behavioral changes in drug addiction. Dopamine receptor antagonist in the BLA blocks cued reinstatement of drug seeking behavior (See et al., 2001). Likewise,
BLA projections to the nucleus accumbens
Neurotransmission between the BLA and NAc is critically involved in reward-seeking behavior and conditioned reinforcement (Everitt et al., 1999). The BLA sends a dense glutamatergic projection to inhibitory medium spiny neurons in the shell and core of the NAc (Fig. 1B) (Kelley et al., 1982, French and Totterdell, 2003, Britt et al., 2012). Interestingly, other striatal sub-regions such as the dorsal medial and dorsal lateral striatum receive substantially less BLA innervation (Stuber et al.,
Role of BNST in addiction
The BNST is considered to be a connective center between stress regions, including the BLA, CeA, medial amygdala (MeA) and the paraventricular nucleus of the hypothalamus (PVN), and brain reward centers, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc) (Silverman et al., 1981, Brog et al., 1993, Georges and Aston-Jones, 2001, Georges and Aston-Jones, 2002, Jalabert et al., 2009). Importantly, the BNST is a critical modulator of addiction-like behavior (Aston-Jones and
Glutamatergic and GABAergic inputs to the BNST
The BNST receives dense glutamatergic and GABAergic innervation from widespread brain regions. Major excitatory inputs to the BNST include several cortical projections including the caudal infralimbic cortex, prelimbic cortex, insula cortex, entrorhinal cortex, and caudal orbital PFC (Fig. 2A) (McDonald, 1998). Additional glutamate inputs arise from the hippocampus via the ventral subiculum, the BLA, parabrachial nucleus, the accessory olfactory bulb and the main olfactory bulb (Fig. 2A) (
BNST projections to the ventral tegmental area
The BNST sends both a GABAergic and glutamatergic projection to the VTA, as observed in retrograde tracing and electrophysiological studies (Fig. 2B) (Cullinan et al., 1993, Georges and Aston-Jones, 2001, Georges and Aston-Jones, 2002, Jalabert et al., 2009), although a recent study using retrograde tracing and electron microscopy techniques showed that this projection is primarily GABAergic (Kudo et al., 2012). Recently, we demonstrated that these GABAergic and glutamatergic BSNT projection
Concluding remarks
While the studies discussed above imply a critical role for BLA and BNST connectivity in different aspects of drug addiction, there remains a great lack of understanding for which specific inputs or outputs are being activated or modulated and under what particular behavioral conditions. Further studies of the functional connectivity within these circuits, including the use of innovative techniques such as pharmacogenetic and optogenetic tools, may provide clinically relevant insight into the
Acknowledgments
We are supported by The Whitehall Foundation, NARSAD, The Foundation of Hope, and NIH grants DA029325 and DA032750 (G.D.S.), AA018610 and AA007573 (D.R.S.), and NS007431 and DA034472 (A.M.S.)
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