Faculty Bibliography

Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.

Sexual, parental, and aggressive behaviors are central to the reproductive success of individuals and species survival and thus are supported by hardwired neural circuits. The reproductive behavior control column (RBCC), which comprises the medial preoptic nucleus (MPN), the ventrolateral part of the ventromedial hypothalamus (VMHvl), and the ventral premammillary nucleus (PMv), is essential for all social behaviors. The RBCC integrates diverse hormonal and metabolic cues and adjusts an animal's physical activity, hence the chance of social encounters. The RBCC further engages the mesolimbic dopamine system to maintain social interest and reinforces cues and actions that are time-locked with social behaviors. We propose that the RBCC and brainstem form a dual-control system for generating moment-to-moment social actions. This Review summarizes recent progress regarding the identities of RBCC cells and their pathways that drive different aspects of social behaviors.

Sexual and aggressive behaviors are vital for species survival and individual reproductive success. Although many limbic regions have been found relevant to these behaviors, how social cues are represented across regions and how the network activity generates each behavior remains elusive. To answer these questions, we utilize multi-fiber photometry (MFP) to simultaneously record Ca²⁺ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting. We find that conspecific sensory information and social action signals are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in the network functional connectivity during the social action initiation phase, whereas late copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRAB_OT1.0. In contrast to previous methods, GRAB_OT1.0 enables imaging of OT release ex vivo and in vivo with suitable sensitivity, specificity and spatiotemporal resolution. Using this sensor, we visualize stimulation-induced OT release from specific neuronal compartments in mouse brain slices and discover that N-type calcium channels predominantly mediate axonal OT release, whereas L-type calcium channels mediate somatodendritic OT release. We identify differences in the fusion machinery of OT release for axon terminals versus somata and dendrites. Finally, we measure OT dynamics in various brain regions in mice during male courtship behavior. Thus, GRAB_OT1.0 provides insights into the role of compartmental OT release in physiological and behavioral functions.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state^1,2. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring^3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits^5,6, we use the medial preoptic area (MPOA), a key site for maternal behaviours^7-11, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTpr^ESR1) are necessary, sufficient and naturally activated during infanticide in female mice. MPOA^ESR1 and BNSTpr^ESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOA^ESR1 and BNSTpr^ESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.

Aggression is costly and requires tight regulation. Here we identify the projection from estrogen receptor alpha-expressing cells in the caudal part of the medial preoptic area (cMPOA^Esr1) to the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential pathway for modulating aggression in male mice. cMPOA^Esr1 cells increase activity mainly during male-male interaction, which differs from the female-biased response pattern of rostral MPOA^Esr1 (rMPOA^Esr1) cells. Notably, cMPOA^Esr1 cell responses to male opponents correlated with the opponents' fighting capability, which mice could estimate based on physical traits or learn through physical combats. Inactivating the cMPOA^Esr1-VMHvl pathway increased aggression, whereas activating the pathway suppressed natural intermale aggression. Thus, cMPOA^Esr1 is a key population for encoding opponents' fighting capability-information that could be used to prevent animals from engaging in disadvantageous conflicts with superior opponents by suppressing the activity of VMHvl cells essential for attack behaviors.

Insulin crosses the blood-brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor-nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states.

Reproduction is the biological process by which new individuals are produced by their parents. It is the fundamental feature of all known life and is required for the existence of all species. All mammals reproduce sexually, a process that involves the union of two reproductive cells, one from a male and one from a female. Sexual behaviors are a series of actions leading to reproduction. They are composed of appetitive, action, and refractory phases, each supported by dedicated developmentally-wired neural circuits to ensure high reproduction success. In rodents, successful reproduction can only occur during female ovulation. Thus, female sexual behavior is tightly coupled with ovarian activity, namely the estrous cycle. This is achieved through the close interaction between the female sexual behavior circuit and the hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will summarize our current understanding, learned mainly in rodents, regarding the neural circuits underlying each phase of the female sexual behaviors and their interaction with the HPG axis, highlighting the gaps in our knowledge that require future investigation.

The neuromodulator dopamine (DA) is essential for regulating learning, motivation, and movement. Despite its importance, however, the mechanisms by which DA influences the activity of target cells to alter behavior remain poorly understood. In this review, we describe recent methodological advances that are helping to overcome challenges that have historically hindered the field. We discuss how the employment of these methods is shedding light on the complex dynamics of extracellular DA in the brain, as well as how DA signaling alters the electrical, biochemical, and population activity of target neurons in vivo. These developments are generating novel hypotheses about the mechanisms through which DA release modifies behavior.

Sexual behavior is fundamental for the survival of mammalian species and thus supported by dedicated neural substrates. The ventrolateral part of ventromedial hypothalamus (VMHvl) is an essential locus for controlling female sexual behaviors, but recent studies revealed the molecular complexity and functional heterogeneity of VMHvl cells. Here, we identify the cholecystokinin A receptor (Cckar)-expressing cells in the lateral VMHvl (VMHvll^Cckar) as the key controllers of female sexual behaviors. The inactivation of VMHvll^Cckar cells in female mice diminishes their interest in males and sexual receptivity, whereas activating these cells has the opposite effects. Female sexual behaviors vary drastically over the reproductive cycle. In vivo recordings reveal reproductive-state-dependent changes in VMHvll^Cckar cell spontaneous activity and responsivity, with the highest activity occurring during estrus. These in vivo response changes coincide with robust alternation in VMHvll^Cckar cell excitability and synaptic inputs. Altogether, VMHvll^Cckar cells represent a key neural population dynamically controlling female sexual behaviors over the reproductive cycle.