Review
Amygdalostriatal projections in the neurocircuitry for motivation: a neuroanatomical thread through the career of Ann Kelley

https://doi.org/10.1016/j.neubiorev.2012.11.019Get rights and content

Abstract

In MacLean's triune brain, the amygdala putatively subserves motivated behavior by modulating the “reptilian” basal ganglia. Accordingly, Ann Kelley, with Domesick and Nauta, influentially showed that amygdalostriatal projections are much more extensive than were appreciated. They highlighted that amygdalar projections to the rostral ventromedial striatum converged with projections from the ventral tegmental area and cingulate cortex, forming a “limbic striatum”. Caudal of the anterior commissure, the entire striatum receives afferents from deep basal nuclei of the amygdala. Orthologous topographic projections subsequently were observed in fish, amphibians, and reptiles. Subsequent functional studies linked acquired value to action via this neuroanatomical substrate. From Dr. Kelley's work evolved insights into components of the distributed, interconnected network that subserves motivated behavior, including the nucleus accumbens shell and core and the striatal-like extended amygdala macrostructure. These heuristic frameworks provide a neuroanatomical basis for adaptively translating motivation into behavior. The ancient amygdala-to-striatum pathways remain a current functional thread not only for stimulus–response valuation, but also for the psychopathological plasticity that underlies addiction-related memory, craving and relapse.

Highlights

► Ann Kelley studied functionally distinct direct vs. indirect amygdalostriatal pathways. ► The entire caudal striatum receives afferents from deep basal amygdalar nuclei. ► The rostral ventromedial striatum differentially receives amygdalar input. ► The ancient amygdala-to-striatum pathways participate in stimulus–response valuation. ► Plasticity in the pathways underlies addiction-related memory, craving and relapse.

Introduction

The amygdala, not included in early conceptualizations of the neurocircuitry of emotion (Bard and Rioch, 1937, Bard, 1928, Cannon, 1931, Papez, 1937), is now a recognized substrate for emotional behavior. In the late-1930s, Klüver and Bucy, 1937, Klüver and Bucy, 1939 described that bilateral temporal lobectomy in rhesus monkeys led to docility, decreased emotional reactivity, increased exploratory behavior, and object-inappropriate sexuality, hyperphagia, and hyperorality, findings that overlapped those of Brown and Schäfer five decades earlier (Brown and Schäfer, 1888). In the 1940s, more specific, bilateral amygdala lesions in cats by Spiegel et al. (1940) and then Bard and Mountcastle (1948) elicited rage behavior, further implicating a role for this structure in modulating emotional behavior. Accordingly, MacLean, 1949, MacLean, 1952, in his triune brain model, included the amygdala in his “paleomammalian limbic system,” which he hypothesized subserved motivated and emotional behavior by modulating activity of the “reptilian” basal ganglia.

Subsequent studies confirmed that lesions that involve the amygdaloid complex “tamed” animals, increased “fearlessness,” increased nonspecific overeating, and produced a deficit in motivated behavior colloquially referred to as “amygdala hangover” (Green et al., 1957, Rosvold et al., 1954, Schreiner and Kling, 1953, Walker et al., 1953, Weiskrantz, 1956, Woods, 1956). Conversely, electrical stimulation of the amygdala potentiated flight and defense reactions (de Molina and Hunsperger, 1959, Ursin and Kaada, 1960). As a result, Weiskrantz (1956) influentially hypothesized that amygdala lesions make it difficult for animals to identify the affective or reinforcing properties of stimuli, dissociating a stimulus’ value from its sensory representation.

Ann Kelley, with Ned Kalin and colleagues at the University of Wisconsin, later offered support to this view by showing that bilateral amygdala destruction in rhesus monkeys blunted fear responses to discrete naturalistic stimuli (Kalin et al., 2001). Lesioned monkeys were less likely to withdraw to the back of their enclosure or delay retrieval of a food treat when exposed to a snake stimulus. Lesioned monkeys were also less likely to exhibit fear grimaces, submit, or perform coo or bark vocalizations when exposed to a threatening adult male conspecific. This study was unique from preceding lesion studies in nonhuman primates because it involved ibotenic acid destruction of cell bodies to spare fibers of passage and used magnetic resonance imaging to guide the site-specificity of the lesion. As such, together with a contemporary study (Meunier et al., 1999), it made a key contribution by linking similar findings from lesion studies in rodents with the emerging human neuroimaging literature (Kalin et al., 2001).

Nonetheless, following Weiskrantz’ hypothesis that the amygdala influences emotional behavior by encoding a stimulus’ sensory representation with value, the circuitry through which the amygdala might accomplish this remained unclear. Gloor, 1955a, Gloor, 1955b had surmised in 1955 that the amygdala modulates “complex somatic, autonomic and behavioral mechanisms integrated in subcortical structures”. Many studies emphasized amygdalar projections that involved the hypothalamus or mediodorsal thalamus via the stria terminalis (de Molina and Hunsperger, 1959, Egger and Flynn, 1962, Egger and Flynn, 1963, Egger and Flynn, 1967, Fox, 1943, Hall, 1963, Kling and Hutt, 1958, Lammers and Lohman, 1957, Nauta, 1961).

Section snippets

Identification of amygdalostriatal projections

Other neuroanatomical evidence, however, supported MacLean's view that the limbic amygdala might directly modulate activity of the basal ganglia (MacLean, 1952). Indeed, Gurdjan wrote in 1928 that the caudate–putamen could not be differentiated from the amygdaloid complex in caudal rat brain sections. By tracing fiber degeneration after electrolytic lesions, Fukuchi (1952) described amygdala projections in ungulates, including a medial stria terminalis component that courses ventromedially into

Cortical-like, topographic projection of basal amygdala to dorsal and ventral striatum

Prior to Kelley's detailed analysis, limited anatomical (Fukuchi, 1952, Lammers and Lohman, 1957, Royce, 1978, Veening et al., 1980, Williams, 1953) and electrophysiological (Dafny et al., 1975) evidence had linked the amygdala to the dorsal striatum. Since then, much has been learned. Russchen, Price, and colleagues, using anterograde techniques in the rat (phytohemagglutinin-L [PHA-L]) and cynomolgus monkey (tritiated amino acids), made observations consistent with those of Kelley of

Amygdalo-ventrostriatal projections: focus on the nucleus accumbens

While Kelley and colleagues’ paper demonstrated that basal amygdala nuclei project to what had, until then, been considered “non-limbic” caudal striatum, it was also influential for further characterizing the already known connection from the amygdala to the rostral ventral striatum (Cowan et al., 1965, De Olmos and Ingram, 1972, Gloor, 1955a, Groenewegen et al., 1980, Ishikawa et al., 1969, Ito et al., 1974, Knook, 1966, Krettek and Price, 1978, Nauta, 1961, Newman and Winans, 1980, Powell et

Extended amygdala: an indirect pathway from the amygdala to extrapyramidal motor system

In parallel to the direct BLA–striatal projections described by Kelley and colleagues, the neuroanatomical entity termed the extended amygdala (Heimer and Alheid, 1991) is a striatal-like substrate that indirectly conveys motivational information from the amygdala to extrapyramidal motor systems (Alheid, 2003). An extended amygdala basal forebrain macrostructure was originally suggested by Johnston (1923) and can be heuristically differentiated into central vs. medial divisions that differ in

Compartmental organization of amygdalo-accumbens projections

During the time that the extended amygdala was first proposed to be a macrostructure, it was also becoming evident that the NAc was composed of functionally distinct subdivisions, with its caudal three-fourths consisting of a pericommisural “core” enveloped on its medial, ventral, and lateral boundaries by a “shell”. These compartments show differences in molecular content, cytoarchitecture, synaptic organization, connectivity, and functional properties (Zahm and Brog, 1992). For example, as

Ancient, conserved amygdalo-striatal circuitry

In addition to mammals (including rats, cats, hamsters, primates, and mice; Novejarque et al., 2011, Ubeda-Banon et al., 2007), orthologous amygdalo-striatal projections have now been described in opossum (McDonald and Culberson, 1986), fish (Lau et al., 2011, Northcutt, 2006), newts (Dube et al., 1990, Marin et al., 1997), frogs (Marin et al., 1997), and lizards (Gonzalez et al., 1990, Martinez-Garcia et al., 1993, Novejarque et al., 2004). For example, in frogs (Xenopus laevis, Rana perezi),

BLA–NAc transmission and plasticity

Across species (Gorbachevskaia, 1992, Gorbachevskaia, 1997, Johnson et al., 1994), dopaminergic afferents from the VTA converge postsynaptically on the same dendritic field of medium-spiny neurons in the NAc on which BLA neurons form excitatory synapses (Stuber et al., 2011). High-frequency electrical stimulation of the BLA in awake rats elicited glutamate and dopamine efflux in the NAc (Jackson and Moghaddam, 2001). Accordingly, optical stimulation of channelrhodopsin-2-transduced BLA

Functional co-connectivity and convergence of BLA with other NAc afferents

Corresponding to the reviewed BLA–NAc topography, more caudal neurons in the BLA also co-target the medial NAc and prelimbic cortex, more rostral neurons co-target the lateral NAc and dorsal agranular insular cortex, and intermediate neurons co-target the lateral NAc and medial NAc (Shinonaga et al., 1994). Within a compartmental framework, the convergence of prelimbic cortex, hippocampal, and ventral subicular afferents with BLA afferents is seen within heterogeneous cell clusters of the

Functional significance of amygdala–ventrostriatal pathways

What aspects of emotional behavior do amygdalo-striatal projections help subserve in coordination with the converging, interactive cortico-striatal, thalamo-striatal, hippocampal–striatal, and ascending midbrain–striatal pathways? As reviewed earlier, Weiskrantz (1956) hypothesized that the amygdala helps associate a stimulus’ affective value to its sensory representation. Consistent with a role for the amygdala in stimulus valuation, behavioral responses to negative reward prediction errors

“Light side” of the central extended amygdala

In addition to playing a role in the reinforcing effects of food as shown by the Kelley laboratory (Andrzejewski et al., 2004, Andrzejewski et al., 2005), the central extended amygdala plays a key role in the acute, primary reinforcing effects of drugs of abuse. For example, local administration of dopamine D1 receptor antagonists directly into the medial NAc, CeA (Caine et al., 1995), and lateral BNST (Epping-Jordan et al., 1998) reduced intravenous cocaine self-administration. Similarly, the

Conclusion

Thus, the original hypothesis of MacLean that the amygdala was a key part of the “paleomammalian limbic system” that adaptively modulates activity of the “reptilian” basal ganglia was transitioned to modern neurobiology by the pioneering work of Ann Kelley and her associates. From her work with Nauta and later with her own team, a clearer picture evolved on the motivational significance of BLA projections to the ventral striatum and the extended amygdala macrostructure. Direct

Conflict of interest statement

EPZ and GFK are co-inventors on a patent for the composition and use of non-peptide CRF1 receptor antagonists (US20100249138), and EPZ is co-inventor on a patent for ghrelin-related anti-obesity treatments (US20100021487).

Acknowledgments

This work was funded by National Institutes of Health grants DK026741, DK70118, DA004043, DA004398, DA010072, DA023957, AA006420, and AA008459 and the Pearson Center for Alcoholism and Addiction Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, or the National Institute on Drug Abuse. We thank Mary

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