Elsevier

Progress in Neurobiology

Volume 130, July 2015, Pages 29-70
Progress in Neurobiology

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

https://doi.org/10.1016/j.pneurobio.2015.03.005Get rights and content

Highlights

  • VP contains several GABAergic subregions with distinct neuronal circuits.

  • Additional circuits arise from nonGABAergic (e.g., glutamatergic) neuronal phenotypes.

  • Dorsolateral VP neurons are sensitive to and necessary for drug-seeking responses.

  • Ventromedial VP neurons discriminate conditions of reward acquisition and consumption.

  • VP is an information integrator capable of dysregulation induced by drugs of abuse.

Abstract

The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally relevant stimuli and coherent adaptive behaviors.

Introduction

More than four decades ago, the ventral pallidum (VP) was delineated from the subcommissural part of the substantia innominata by Heimer and colleagues (Heimer, 1972, Heimer and Wilson, 1975, Switzer et al., 1982, Heimer et al., 1982). In early discussions, Mogenson et al. (1980) proposed that the VP integrated limbic/emotionally salient signals from the nucleus accumbens (Acb) to brain motor systems. Swerdlow and Koob (1987) furthered this hypothesis with studies showing how the Acb to VP projection links the mesoaccumbal dopamine system to motor circuitry. At the time, dopamine was already well-known to be involved in reward-motivated behavior (Wise, 1980). Soon after, it was revealed that the VP is innervated by dopamine inputs from the midbrain and that dopamine directly alters VP neuronal firing (Napier and Potter, 1989). As early as 1991, Napier and colleagues (1991a) put forth the concept that in addition to integrating various inputs from Acb, the VP incorporates reward-related signals carried by midbrain dopaminergic neurons. This concept was quickly expanded to encompass the idea that dopamine transmission within the VP regulates a collection of behaviors, including locomotion and cognition (Napier, 1992c). Building on the role of VP dopamine, and Mogenson's original concepts involving the VP in brain circuits that direct “motivation to action” (Mogenson et al., 1980), it was subsequently proposed that the VP forms part of a “final common pathway” for drug-seeking behavior (Kalivas and Volkow, 2005) and for reward processing in general (Smith et al., 2009). These concepts served as modern-day assessments of the ventral striatopallidal system. As our understanding of this system has grown, the importance of subregional circuits involving the ventromedial VP (VPvm) and dorsolateral VP (VPdl) with the Acb shell (AcbSh) and Acb core (AcbC) has become apparent. Furthermore, although considered a largely inhibitory structure, a substantial proportion of neurons residing in VP express vesicular glutamate transporter 2 (VGluT2) mRNA (Hur and Záborszky, 2005), indicating subpopulations of VP neurons have the capacity for glutamatergic neurotransmission. In addition, the cholinergic neurons residing within VP receive GABAergic input from the Acb (Zaborszky and Cullinan, 1992), make local connections within VP as well as extrinsic projections to the prefrontal cortex and the basolateral amygdala. Therefore, the goal of this review is to provide a new conceptual framework for the VP that incorporates current understanding of its subregional afferents, efferents, neuronal function and the roles for its subregions and neuronal phenotypes in behavior.

We put forth that the contribution of VP toward a variety of motivated behaviors is dependent upon the participation of GABAergic neurons belonging to individual VP subregions, as well as from nonGABAergic neurons, which affect discrete neuronal circuits. GABAergic VPvm neurons, with AcbSh afferents and thalamocortical, dopaminergic, and hypothalamic targets, are involved in discriminating the stimulus conditions of reward/drug acquisition, consumption, and working memory. NonGABAergic VP neurons, with dopaminergic and cortical targets, provide excitatory signals that likely oppose the VPvm-mediated signals. GABAergic VPdl neurons innervated by AcbC neurons and projecting to motor-related structures including subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), are involved in mediating reward motivated behavior (e.g., drug-seeking responses). VP circuits adapt to repeated exposure to reward-related stimuli (e.g., repeated drug use), and these adaptations alter the integrative capacity of the VP which can lead to alterations in the output of motivation and reward. Thus, understanding the subregional neuroanatomy of the VP, and its related circuits, will broaden our understanding on the underpinnings of such behavioral dysfunctions.

Section snippets

Boundaries of the ventral pallidum and its subregional compartmentation

Pallidal brain structures are linked to basal ganglia circuitries. In the basal ganglia, pallidal structures include the globus pallidus (GP), the rodent homolog of the external pallidal segment in higher species, and the entopeduncular nucleus (EPN), the rodent homolog of the internal pallidal segment. The VP occupies the rostral, subcommissural part of the area historically known as the substantia innominata. VP is a major component of the ventral striatopallidal system that is ventral to the

Afferent inputs and changes in firing rates induced by these inputs

In the following subsections we review the afferent connections to the VP subregions and responsiveness of VP neurons to these inputs (Fig. 5). While most of the afferent (and efferent) projection patterns of VP subregions are well delineated, few studies have considered whether or not neurons belonging to distinct VP subregions exhibit differential sensitivity to various afferent-associated transmitters. As such evaluations are critical to understanding the functional circuits in which the VP

Outputs and loops

There is a rich literature that demonstrates the wide array of brain regions which are linked to the VP. In the following subsections we review the efferent connections of VP subregions and neuronal phenotypes (Fig. 5, Fig. 6).

VP influences on behavior

A wealth of information is emerging regarding the roles of VP in behavior and in recent years, subregional dissection of these roles has begun. In the following sections, we overview VP-regulated behaviors, and propose functional roles for the two major VP subregions, VPvm and VPdl. The roles of VPr and VPvl require future investigation. In considering the role of a brain structure in behavior, it is important to be mindful that this may reflect a modulatory function of behaviors that are

Drugs of abuse; influences on VP function and behavior

Neuroscience has come to view drug and alcohol addiction as a chronically relapsing disorder with an impaired ability to inhibit drug-seeking behavior (Kalivas, 2009, Koob and Volkow, 2010). This impairment could arise, in part, from alterations in VP function. It is therefore expected that if abused drugs act within the VP, there may be changes in motivated behavior as well as the processing of cue salience and/or mnemonic events. To discuss these possibilities, this section will overview the

Concluding remarks – differential information flow across VP subregions and neuronal phenotypes

The VP is necessary for a variety of behaviors. Some are adaptive, such as those involving seeking and consuming food or ensuring the health and safety of offspring. Other behaviors are pathological, such as the self-administration of abused drugs. In this review, we put forth the notion that VP regulates these diverse behaviors via unique channels of information processing from GABAergic neurons belonging to individual subregions and from nonGABAergic neuronal phenotypes.

The VPdl, which

Funding

There are no financial interests to be disclosed.

Acknowledgements

This review and the included research were supported by the USPHSGs NS23945 (LZ), DA05255 (TCN) and DA015760 (TCN), and the Intramural Research Program at the National Institute on Drug Abuse (DHR). Research support was also provided by NRSAs to trainees in TCN's laboratory including: F32 DA05651 to P Johnson, F30 MH45180 to MS Turner, F31 DA019763 to F Shen, DA019783 to AL Mickiewicz, DA023306 to AA Herrold, DA021475 to RM Voigt, DA024923 to SM Graves and DA0331231 to SE Tedford. Gratitude is

References (543)

  • A. Bourdelais et al.

    Amphetamine lowers extracellular GABA concentration in the ventral pallidum

    Brain Res.

    (1990)
  • J. Burgdorf et al.

    Neurobiology of 50-kHz ultrasonic vocalizations in rats: electrode mapping, lesion, and pharmacology studies

    Behav. Brain Res.

    (2007)
  • H.T. Chang et al.

    Projection neurons of the nucleus accumbens: an intracellular labeling study

    Brain Res.

    (1985)
  • J.Y. Chang et al.

    Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats

    Brain Res.

    (1997)
  • J.Y. Chang et al.

    Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats

    Neuroscience

    (2000)
  • C.H. Chang et al.

    Amygdala-Ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats

    Biol. Psychiatry

    (2014)
  • L.-W. Chen et al.

    Cholinergic neurons expressing substance P receptor (NK 1) in the basal forebrain of the rat: a double immunocytochemical study

    Brain Res.

    (2001)
  • S. Chen et al.

    Afferent connections of the thalamic paraventricular and parataenial nuclei in the rat – a retrograde tracing study with iontophoretic application of Fluoro-Gold

    Brain Res.

    (1990)
  • J.J. Chrobak et al.

    Basal forebrain infusions impair delayed-non-match-to-sample radial arm maze performance

    Pharmacol. Biochem. Behav.

    (2002)
  • L. Churchill et al.

    The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum

    Behav. Brain Res.

    (1999)
  • L. Churchill et al.

    Changes in gamma-aminobutyric acid, mu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens

    Brain Res.

    (1990)
  • L.C. Conrad et al.

    Autoradiographic tracing of nucleus accumbens efferents in the rat

    Brain Res.

    (1976)
  • P.C. Contreras et al.

    Autoradiographic distribution of non-dopaminergic binding sites labeled by [3H]haloperidol in rat brain

    Neurosci. Lett.

    (1987)
  • A.R. Cools et al.

    Anatomically distinct output channels of the caudate nucleus and orofacial dyskinesia: critical role of the subcomissural part of the globus pallidus in oral dyskinesia

    Neuroscience

    (1989)
  • I.R. Covelo et al.

    Manipulation of GABA in the ventral pallidum, but not the nucleus accumbens, induces intense, preferential, fat consumption in rats

    Behav. Brain Res.

    (2014)
  • J.A. Danks et al.

    A comparative autoradiographic study of the distributions of substance P and eledoisin binding sites in rat brain

    Brain Res.

    (1986)
  • E. De Leonibus et al.

    Locomotor activity induced by the non-competetive N-methyl-d-aspartate antagonist, MK-801: role of nucleus accumbens efferent pathways

    Neuroscience

    (2001)
  • F. Del-Fava et al.

    Efferent connections of the rostral linear nucleus of the ventral tegmental area in the rat

    Neuroscience

    (2007)
  • P. Di Ciano

    Distinct contributions of dopamine receptors in the nucleus accumbens core or shell to established cocaine reinforcement under a second-order schedule

    Eur. Neuropsychopharmacol.

    (2008)
  • E.K. Diekhof et al.

    A function neuroimaging study assessing gender difference in the neural mechanism underlying the ability to resiste impulsive desires

    Brain Res.

    (2012)
  • J.A. Echo et al.

    Alterations in food intake elicited by GABA and opioid agonists and antagonists administered into the ventral tegmental area region of rats

    Physiol. Behav.

    (2002)
  • A.M. Farrar et al.

    Forebrain circuitry involved in effort-related choice: injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior

    Neuroscience

    (2008)
  • M.W. Feltenstein et al.

    NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

    Neurobiol. Learn. Mem.

    (2007)
  • M. Filip et al.

    Serotonin 5-HT(2C) receptors in nucleus accumbens regulate expression of the hyperlocomotive and discriminative stimulus effects of cocaine

    Pharmacol. Biochem. Behav.

    (2002)
  • P.J. Fletcher et al.

    Injections of d-amphetamine into the ventral pallidum increase locomotor activity and responding for conditioned reward: a comparison with injections into the nucleus accumbens

    Brain Res.

    (1998)
  • P.S. Frankel et al.

    Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users

    Neuropharmacology

    (2008)
  • J.E. Alesdatter et al.

    Inhibition of mu opioid-induced motor activity in the ventral pallidum by D1 receptor blockade

    Behav. Pharmacol.

    (1993)
  • G.E. Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annu. Rev. Neurosci.

    (1986)
  • G.F. Alheid

    Extended amygdala and basal forebrain

    Ann. N. Y. Acad. Sci.

    (2003)
  • A.T. Alleweireldt et al.

    Effects of SCH-23390 infused into the amygdala or adjacent cortex and basal ganglia on cocaine seeking and self-administration in rats

    Neuropsychopharmacology

    (2006)
  • N.M. Appel et al.

    Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain

    J. Pharmacol. Exp. Ther.

    (1990)
  • M.C. Austin et al.

    Enkephalinergic and GABAergic modulation of motor activity in the ventral pallidum

    J. Pharmacol. Exp. Ther.

    (1990)
  • I. Avila et al.

    Distinct neuronal populations in the basal forebrain encode motivational salience and movement

    Front. Behav. Neurosci.

    (2014)
  • I. Avila et al.

    Motivational salience signal in the basal forebrain is coupled with faster and more precise decision speed

    PLoS Biol.

    (2014)
  • D.A. Baker et al.

    The origin and neuronal function of in vivo nonsynaptic glutamate

    J. Neurosci.

    (2002)
  • D.A. Baker et al.

    Neuroadaptations in cystine–glutamate exchange underlie cocaine relapse

    Nat. Neurosci.

    (2003)
  • B.W. Balleine et al.

    Thalamocortical integration of instrumental learning and performance and their disintegration in addiction

    Brain Res.

    (2014)
  • D.J. Barker et al.

    Sensitivity to self-administered cocaine within the lateral preoptic-rostral lateral hypothalamic continuum

    Brain Struct. Funct.

    (2014)
  • D.J. Barker et al.

    Ultrasonic vocalizations: evidence for an affective opponent process during cocaine self-administration

    Psychopharmacology (Berl.)

    (2014)
  • D.J. Barker et al.

    Dose-dependent differences in short ultrasonic vocalizations emitted by rats during cocaine self-administration

    Psychopharmacology (Berl.)

    (2010)
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