Ingestive Classics
Ann E. Kelley and Nucleus Accumbens ‘Supervision’ of the Hypothalamus

Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus.
Journal of Neuroscience 15, 6779-6788, 1995.

Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior.
Journal of Neuroscience 19, 11040-11048, 1999.

Comments by Brian A. Baldo, (Jan. 18, 2023)

Dr. Ann E. Kelley (1954-2007) was one of the most influential neuroscientists of her generation. Among many seminal contributions, her work helped define our contemporary understanding of how forebrain systems regulate feeding behavior. I’ve selected as classics two papers that document her discovery of the functional relationship between the lateral hypothalamus (LH), and a subregion of the nucleus accumbens, the medial ‘shell’ (AcbSh)[1, 2]. It is now well-accepted that these sites form an interactive circuit through which AcbSh governs feeding-modulatory hypothalamic systems. This discovery unified two major research domains in the ingestive behavior field: the regulatory controls exerted by the hypothalamus, and the affective and motivational controls exerted by telencephalic and limbic structures. Ann’s discovery of the AcbSh-LH interaction has withstood the test of time, and it spawned a still-active research area. These two classics documented profound feeding-related effects after localized pharmacological blockade of AMPA-type glutamate receptors [1] or stimulation of GABA systems [2] in the medial part of the AcbSh. These manipulations provoked a voracious feeding response in sated rats, ranking among the most dramatic drug-induced feeding responses produced anywhere in the brain. Remarkably, these feeding responses were nearly completely suppressed by concomitant inhibition of the LH. Related work showed that intra-AcbSh GABA stimulation strongly activated the LH (as indexed by expression of the immediate-early gene, Fos) [2].

My reason for selecting these papers is to highlight Ann’s focus on synthesizing the behavioral and anatomical levels of analysis. In fact, she often would say that good insight into neural function is inseparable from good knowledge of anatomy. This outlook originated in her early training with Drs. Susan Iversen and Walle Nauta. Nauta’s perspective was that regional behavioral specializations of the striatum reflected (at least in part) those of their respective cortical afferents [3]. Armed with this framework and using powerful pharmacological and behavioral techniques from the Iversen lab [4], Ann developed a comprehensive research program to determine the roles of neo- and allo-cortical afferents in the behavioral heterogeneity of the striatum. This research program eventually led Ann to a curious subregion of the ventral striatum, the AcbSh.

Why is the AcbSh a bit odd, and what does that have to do with feeding? Roughly contemporaneously with the papers discussed here, anatomical understanding of basal forebrain organization was being transformed by the work of Lennart Heimer and colleagues. Their meticulous studies revealed an anatomical continuum that emanates rostro-medially from the central amygdala and winds up at the bed nucleus of the stria terminalis, abutting the caudal AcbSh [5, 6]. Heimer and colleagues proposed that this swath of basal forebrain is developmentally and hodologically related to the central amygdala, and they termed it the ‘extended amygdala’ (EA) [5]. It is now understood that the AcbSh represent a transitional zone between ventral striatum and EA, blending canonical striato-pallidal-thalamic circuitry with some decidedly non-striatal projections [7, 8]. Notable among these is a direct projection from the AcbSh to the hypothalamus [e.g., 7, 9-11], which provides a compellingly parsimonious route through which reward-related processing in the Acb could regulate hypothalamic substrates [12, 13].

Ann’s early anatomy work had also provided insights on the unique circuitry relationships of the AcbSh, but on the afferent side. She had published a foundational paper (with V. Domesick) on hippocampal innervation of the Acb, in which they documented a circumscribed hippocampal terminal field in the medial AcbSh [14]. Ann’s discovery of the feeding-modulatory role of the medial AcbSh arose somewhat serendipitously from an interest in exploring this hippocampus-innervated sector of AcbSh. A talented graduate student, Carmen Maldonado-Irizzary (now Maldonado-Vlaar), began a mapping study of the effects of local injections of glutamate receptor antagonists on spatial learning and other behaviors. This work resulted in intriguing insights and some of the first papers reporting behavioral differences between the Acb core and shell [15, 16].

But Carmen noticed something remarkable: the rats ate voraciously upon being returned to their home cages after testing. This led to Carmen and Ann’s [1] discoveries that infusions of AMPA antagonists produced a short-latency, intense feeding response. An analysis of the injector placements yielding this remarkable effect revealed that the most sensitive site was the medial shell subregion [1, 17]. Ann immediately realized that this was likely related to AcbSh’s unusual anatomical relationship to the LH. She and Carmen devised a set of experiments using an elegant dual-cannulation approach and demonstrated that inactivating the LH essentially wiped out the AcbSh-driven effect [1].

These results were later extended by Ann and another talented trainee, Dr. Tom Stratford. Tom examined whether GABA-mediated inhibition would produce effects like those of AMPA blockade, as one would expect if the key variable determining the hyperphagic response were net diminution of AcbSh activity. As mentioned above, GABA receptor stimulation (again, in a circumscribed zone of the medial AcbSh) elicited a similarly elevated feeding response, was blocked at the level of the LH [2], and provoked intense Fos expression in the same LH zones where pharmacological inactivation had blocked the hyperphagia [2]. Hence, AcbSh inhibition was sufficient to activate hypothalamic systems, and hypothalamic activation was necessary for the AcbSh-mediated feeding effect. A further interesting insight that emerged from this work was that, because local hypothalamic glutamate receptor blockade reversed AcbSh-driven feeding, a glutamate synapse must be interposed between the AcbSh efferents and the ultimate hypothalamic feeding actuators. Nevertheless, the fundamental ideas, that the AcbSh represents a specialized feeding-modulatory zone of the striatum and that this role is determined by a functional interaction with the LH, were upheld.

Based on these results, Ann proposed that the AcbSh plays a ‘supervisory’ role over hypothalamic function, in which fluctuations in glutamate- or GABA-driven AcbSh activity could rapidly activate or suppress feeding-regulatory hypothalamic regions in alignment with internal states and external stimuli. In this context, she described the AcbSh as a ‘sensory sentinel’ whose function would help animals switch between feeding and competing reconnaissance behaviors, particularly in environmental contexts where vigilance is required [18-20]. Because of her premature death from cancer in 2007, Ann never witnessed the opto- and chemo-genetic revolutions that provided ways to reversibly modulate individual projection pathways in vivo, thus permitting inferences regarding the causal role of a particular pathway in behavior. She would have been delighted to see how these methods led to extensions of her pioneering finding and bolstered her theoretical model [21-25].

On a personal note, I recall Ann’s excitement at the breakthrough study with Carmen. She had organized a trainee dinner at a Society for Neuroscience meeting, and we were all discussing life, the Universe, and everything (but especially science). I recall that margaritas were on the scene… But mostly, I recall Ann laying out the entire anatomical context outlined above, and more---she incorporated the classic LH lesion studies, hypothalamic self-stimulation studies, and how her own career trajectory was decided one day as a student at the University of Pennsylvania, upon observing an in-class demonstration of a rat self-stimulating its LH. “I needed to find out how that works!” she told us. It was a master class in which Ann effortlessly connected decades of foundational neuroscience with our current work, in a captivating, inspiring and personal way, imbued with her irrepressible enthusiasm and love of science.


1. Maldonado-Irizarry, C.S., C.J. Swanson, and A.E. Kelley, Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus. J Neurosci, 1995. 15(10): p. 6779-88.

2. Stratford, T.R. and A.E. Kelley, Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior. J Neurosci, 1999. 19(24): p. 11040-8.

3. Mehler, W.R. and W.J. Nauta, Connections of the basal ganglia and of the cerebellum. Confin Neurol, 1974. 36(4-6): p. 205-22.

4. Kelley, A.E., L. Stinus, and S.D. Iversen, Behavioural activation induced in the rat by substance P infusion into ventral tegmental area: implication of dopaminergic A10 neurones. Neurosci Lett, 1979. 11(3): p. 335-9.

5. Alheid, G.F. and L. Heimer, New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience, 1988. 27(1): p. 1-39.

6. de Olmos, J.S. and L. Heimer, The concepts of the ventral striatopallidal system and extended amygdala. Ann N Y Acad Sci, 1999. 877: p. 1-32.

7. Heimer, L., et al., Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience, 1991. 41(1): p. 89-125.

8. Heimer, L., et al., The accumbens: beyond the core-shell dichotomy. J Neuropsychiatry Clin Neurosci, 1997. 9(3): p. 354-81.

9. Sano, H. and M. Yokoi, Striatal medium spiny neurons terminate in a distinct region in the lateral hypothalamic area and do not directly innervate orexin/hypocretin- or melanin-concentrating hormone containing neurons. J Neurosci, 2007. 27(26): p. 6948-55.

10. Zheng, H., L.M. Patterson, and H.R. Berthoud, Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J Neurosci, 2007. 27(41): p. 11075-82.

11. Thompson, R.H. and L.W. Swanson, Hypothesis-driven structural connectivity analysis supports network over hierarchical model of brain architecture. Proc Natl Acad Sci U S A, 2010. 107(34): p. 15235-9.

12. Baldo, B.A., et al., Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur J Neurosci, 2004. 19(2): p. 376-86.

13. Zheng, H., et al., Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons. Am J Physiol Regul Integr Comp Physiol, 2003. 284(6): p. R1436-44.

14. Kelley, A.E. and V.B. Domesick, The distribution of the projection from the hippocampal formation to the nucleus accumbens in the rat: an anterograde- and retrograde-horseradish peroxidase study. Neuroscience, 1982. 7(10): p. 2321-35.

15. Maldonado-Irizarry, C.S. and A.E. Kelley, Differential behavioral effects following microinjection of an NMDA antagonist into nucleus accumbens subregions. Psychopharmacology (Berl), 1994. 116(1): p. 65-72.

16. Maldonado-Irizarry, C.S. and A.E. Kelley, Excitatory amino acid receptors within nucleus accumbens subregions differentially mediate spatial learning in the rat. Behav Pharmacol, 1995. 6(5 And 6): p. 527- 539.

17. Kelley, A.E. and C.J. Swanson, Feeding induced by blockade of AMPA and kainate receptors within the ventral striatum: a microinfusion mapping study. Behav Brain Res, 1997. 89(1-2): p. 107-13.

18. Kelley, A.E., Ventral striatal control of appetitive motivation: role in ingestive behavior and reward related learning. Neurosci Biobehav Rev, 2004. 27(8): p. 765-76.

19. Kelley, A.E., B.A. Baldo, and W.E. Pratt, A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. J Comp Neurol, 2005. 493(1): p. 72-85.

20. Baldo, B.A. and A.E. Kelley, Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding. Psychopharmacology (Berl), 2007. 191(3): p. 439- 59.

21. O'Connor, E.C., et al., Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding. Neuron, 2015. 88(3): p. 553-64.

22. Prado, L., et al., Activation of Glutamatergic Fibers in the Anterior NAc Shell Modulates Reward Activity in the aNAcSh, the Lateral Hypothalamus, and Medial Prefrontal Cortex and Transiently Stops Feeding. J Neurosci, 2016. 36(50): p. 12511-12529.

23. Thoeni, S., et al., Depression of Accumbal to Lateral Hypothalamic Synapses Gates Overeating. Neuron, 2020. 107(1): p. 158-172 e4.

24. Smith, A.E., et al., Glutamatergic projections from homeostatic to hedonic brain nuclei regulate intake of highly palatable food. Sci Rep, 2020. 10(1): p. 22093.

25. Cheng, J., et al., Anterior Paraventricular Thalamus to Nucleus Accumbens Projection Is Involved in Feeding Behavior in a Novel Environment. Front Mol Neurosci, 2018. 11: p. 202.