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