Elsevier

Neuropharmacology

Volume 60, Issue 5, April 2011, Pages 765-773
Neuropharmacology

Invited review
Interneurons in the basolateral amygdala

https://doi.org/10.1016/j.neuropharm.2010.11.006Get rights and content

Abstract

The amygdala is a temporal lobe structure that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala arises from its role in processing fear and the relationship of fear to human anxiety. The amygdaloid complex is divided into a number of subnuclei that have extensive intra and extra nuclear connections. In this review we discuss recent findings on the physiology and plasticity of inputs to interneurons in the basolateral amygdala, the primary input station. These interneurons are a heterogeneous group of cells that can be separated on immunohistochemical and electrophysiological grounds. Glutamatergic inputs to these interneurons form diverse types of excitatory synapses. This diversity is manifest in both the subunit composition of the underlying NMDA receptors as well as their ability to show plasticity. We discuss these differences and their relationship to fear learning.

This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.

Research highlights

► The amygdala is well known to play a key role in emotional processing. ► Dysfunction of the amygdala plays a central role in many anxiety disorders. ► Here we review the inhibitory micro-circuitry of the basolateral amygdala. ► We point out that there are significant differences between the amygdala and cortical inhibitory circuitry. ► Understanding this circuitry may provide novel targets for the treatment of anxiety disorders.

Introduction

The amygdala is a collection of associated nuclei located in the temporal lobe that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala largely arises from its central role in a simple form of learning known as fear conditioning (Davis and Whalen, 2001, Fanselow and Poulos, 2005, LeDoux, 2003). This is a Pavlovian conditioning procedure in which an emotionally neutral stimulus (the conditioned stimulus, CS), such as a tone or light is contingently paired with an aversive one, typically a mild foot shock. After a small number of pairings subjects learn to associate the two stimuli and now respond with fear to the initially neutral CS. This learnt response, the conditioned response (CR), is rapidly acquired and long lasting (Davis, 1992, LeDoux, 2000). As such, the CR results from subjects learning the association between two sensory stimuli, storing this association and subsequent retrieval of the memory in response to sensing the CS. Once a fear memory has been established, it is generally stable for long periods of time, sometimes a lifetime. However, subsequent repeated presentation of the CS gradually reduces the CR, a process known as extinction (Myers and Davis, 2007, Quirk and Mueller, 2008). In extinction, rather than forgetting the initial learning, subjects form new associations that inform them that the previously conditioned CS is no longer threatening. This therefore represents the learning and storage of new memory such that the original CS is no longer perceived as fearful, and the response to the CS is inhibited (Maren and Quirk, 2004, Pape and Pare, 2010, Quirk and Mueller, 2008).

A large body of data has shown that the amygdala is critically involved in the learning, storage and retrieval of both conditioned fear and extinction (Herry et al., 2008, LeDoux, 1995, Pape and Pare, 2010, Sah et al., 2003). Thus, understanding the function of the amygdala, its intrinsic neural circuits, and the molecular mechanisms that underlie fear conditioning will firstly provide insight into the physiological mechanisms of learning and memory formation in the mammalian brain. Secondly, as there are clear similarities between learnt fear and anxiety in humans, it is believed that understanding the mechanisms that underlie fear conditioning and its dysfunction, may provide a window into the cellular mechanisms that underlie the genesis of disorders such as generalized anxiety, depression and post-traumatic stress (Davis and Whalen, 2001, Quirk and Gehlert, 2003). Moreover, treatments like exposure therapy that are used for a variety of anxiety disorders are largely based on extinction protocols (McNally, 2007). Thus, understanding the cellular mechanisms that underlie extinction inform us about the mechanisms that underpin the treatment of anxiety disorders, and suggest possible targets for the development of new therapies.

The nuclei of the amygdaloid complex can be grouped in to three functionally relevant subdivisions: the centromedial, cortical and basolateral groups. These subdivisions can be identified based on their unique connectivity, immunohistochemical and cytoarchitectural profiles. The anatomy and physiology of the amygdala has been reviewed in detail previously (Alheid et al., 1995, McDonald, 1998, Sah et al., 2003, Swanson and Petrovich, 1998). A converging body of data has established that sensory information from both cortical and subcortical regions enters the amygdala at the level of the basolateral nucleus (BLA). This information is processed within the BLA and transmitted to the central nucleus (CeA). Projections from the CeA target hypothalamic and brainstem structures that evoke the conditioned response (Davis and Whalen, 2001, LeDoux, 2000). These two regions, the BLA and the CeA, and their connections play a central role in the formation and recall of memory traces during fear conditioning and extinction (Maren and Quirk, 2004, Pape and Pare, 2010, Pare et al., 2004). Learning and memory formation in the mammalian brain are generally thought to result from synaptic plasticity at glutamatergic synapses (Bliss and Collingridge, 1993). In agreement with this, both fear conditioning and extinction are accompanied by changes at glutamatergic synapses in the amygdala (Pape and Pare, 2010, Sah et al., 2008). However, emerging evidence indicates that GABAergic synapses within the amygdala also play key roles in both fear conditioning and extinction (Ehrlich et al., 2009). For example, enhancers of GABAergic inhibition in the BLA interfere with learning and expression of conditioned fear (Davis, 1979, Harris and Westbrook, 1998) whereas reduction in GABAergic inhibition has the opposite effect (Tang et al., 2007). Moreover, pharmacological agents that modulate anxiety levels are thought to produce their anxiolytic actions by acting at γ-aminobutyric-acid (GABA) receptors within the amygdala (Rudolph and Mohler, 2006).

Section snippets

GABAergic neurons in the amygdala

The amygdaloid complex (Fig. 1) can be described as an interface of cortical and striatal cell lineages (Swanson and Petrovich, 1998, Waclaw et al., 2010). This feature makes a general discussion of GABAergic neurons in the amygdala a tale of two halves. Both developmentally (Waclaw et al., 2010), and structurally (McDonald, 1992), the BLA is a cortical like structure. As with other cortical regions, it contains two main types of neuron: glutamatergic principal neurons and GABAergic

Conclusions

The amygdala is a temporal lobe structure that is involved in emotional processing. In particular it plays a key role in fear learning and extinction. The BLA is the main route by which sensory information enters the amygdala and much of the plasticity that underlies fear learning is thought to occur at synapses in the BLA. The BLA is a cortical like structure that contains glutamatergic principal neurons and local circuit interneurons; however, the local circuitry of the BLA is just beginning

References (118)

  • A.J. McDonald

    Immunohistochemical identification of gamma-aminobutyric acid-containing neurons in the rat basolateral amygdala

    Neurosci. Lett.

    (1985)
  • A.J. McDonald

    Localization of AMPA glutamate receptor subunits in subpopulations of non-pyramidal neurons in the rat basolateral amygdala

    Neurosci. Lett.

    (1996)
  • A.J. McDonald

    Cortical pathways to the mammalian amygdala

    Prog. Brain Res.

    (1998)
  • A.J. McDonald et al.

    Localization of GABA-like immunoreactivity in the monkey amygdala

    Neuroscience

    (1993)
  • A.J. McDonald et al.

    Parvalbumin-containing neurons in the rat basolateral amygdala: morphology and co-localization of Calbindin-D(28k)

    Neuroscience

    (2001)
  • A.J. McDonald et al.

    Colocalization of calcium-binding proteins and GABA in neurons of the rat basolateral amygdala

    Neuroscience

    (2001)
  • A.J. McDonald et al.

    Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons

    Neuroscience

    (2001)
  • A.J. McDonald et al.

    Immunohistochemical characterization of somatostatin containing interneurons in the rat basolateral amygdala

    Brain Res.

    (2002)
  • A.J. McDonald et al.

    Evidence for a perisomatic innervation of parvalbumin-containing interneurons by individual pyramidal cells in the basolateral amygdala

    Brain Res.

    (2005)
  • R.J. McNally

    Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders

    Clin. Psychol. Rev.

    (2007)
  • H. Monyer et al.

    Developmental and regional expression in the rat brain and functional properties of four NMDA receptors

    Neuron

    (1994)
  • D. Pare et al.

    Intrinsic circuitry of the amygdaloid complex: common principles of organization in rats and cats

    Trends Neurosci.

    (1998)
  • D. Pare et al.

    Intra-amygdaloid projections of the basolateral and basomedial nuclei in the cat: Phaseolus vulgaris-leucoagglutinin anterograde tracing at the light and electron microscopic level

    Neuroscience

    (1995)
  • B.D. Philpot et al.

    Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex

    Neuron

    (2001)
  • G.J. Quirk et al.

    Fear conditioning enhances short-latency auditory responses of lateral amygdaloid neurons: parallel recordings in the freely behaving rat

    Neuron

    (1995)
  • S.M. Rodrigues et al.

    Molecular mechanisms underlying emotional learning and memory in the lateral amygdala

    Neuron

    (2004)
  • S. Royer et al.

    Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses

    Neuroscience

    (2002)
  • U. Rudolph et al.

    GABA-based therapeutic approaches: GABAA receptor subtype functions

    Curr. Opin. Pharmacol.

    (2006)
  • G.F. Alheid et al.

    Amygdala and extended amygdala

  • T. Amano et al.

    Synaptic correlates of fear extinction in the amygdala

    Nat. Neurosci.

    (2010)
  • G.A. Ascoli et al.

    Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex

    Nat. Rev. Neurosci.

    (2008)
  • E.P. Bauer et al.

    Heterosynaptic long-term potentiation of inhibitory interneurons in the lateral amygdala

    J. Neurosci.

    (2004)
  • S. Bissiere et al.

    Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition

    Nat. Neurosci.

    (2003)
  • T.V.P. Bliss et al.

    A synaptic model of memory: long term potentiation in the hippocampus

    Nature

    (1993)
  • M. Davis

    Diazepam and flurazepam: effects on conditioned fear as measured with the potentiated startle paradigm

    Psychopharmacology (Berl.)

    (1979)
  • M. Davis

    The role of the amygdala in fear and anxiety

    Annu. Rev. Neurosci.

    (1992)
  • M. Davis et al.

    The amygdala: vigilance and emotion

    Mol. Psychiatry

    (2001)
  • E.C. Dumont et al.

    Physiological properties of central amygdala neurons: species differences

    Eur. J. Neurosci.

    (2002)
  • M.S. Fanselow et al.

    The neuroscience of mammalian associative learning

    Annu. Rev. Psychol.

    (2005)
  • C.R. Farb et al.

    NMDA and AMPA receptors in the lateral nucleus of the amygdala are postsynaptic to auditory thalamic afferents

    Synapse

    (1997)
  • C.R. Farb et al.

    Afferents from rat temporal cortex synapse on lateral amygdala neurons that express NMDA and AMPA receptors

    Synapse

    (1999)
  • T.F. Freund et al.

    Interneurons of the hippocampus

    Hippocampus

    (1996)
  • M. Garcia-Lopez et al.

    Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development

    J. Comp. Neurol

    (2008)
  • J.A. Harris et al.

    Evidence that GABA transmission mediates context-specific extinction of learned fear

    Psychopharmacology (Berl)

    (1998)
  • Y. Hayashi et al.

    Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction

    Science

    (2000)
  • C. Herry et al.

    Switching on and off fear by distinct neuronal circuits

    Nature

    (2008)
  • A.M. Jasnow et al.

    Distinct subtypes of cholecystokinin (CCK)-containing interneurons of the basolateral amygdala identified using a CCK promoter-specific lentivirus

    J. Neurophysiol.

    (2009)
  • I. Katona et al.

    Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission

    J. Neurosci.

    (2001)
  • S. Kemppainen et al.

    Distribution of parvalbumin, calretinin, and calbindin-D(28k) immunoreactivity in the rat amygdaloid complex and colocalization with gamma-aminobutyric acid

    J. Comp. Neurol.

    (2000)
  • T. Klausberger et al.

    Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo

    Nature

    (2003)
  • Cited by (0)

    1

    Present address: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.

    View full text