Faculty Bibliography

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.

Active defense against a conspecific aggressor is essential for survival. Previous studies revealed strong c-Fos expression in the ventrolateral part of the ventromedial hypothalamus (VMHvl) in defeated animals. Here, we examined the functional relevance and in vivo responses of the VMHvl during conspecific defense. We found that VMHvl cells expressing estrogen receptor α (Esr1) are acutely excited during active conspecific defense. Optogenetic inhibition of the cells compromised an animal's ability to actively defend against an aggressor, whereas activating the cells elicited defense-like behaviors. Furthermore, the VMHvl is known for its role in aggression. In vivo recording and c-Fos mapping revealed differential organization of the defense and aggression-responsive cells in the VMHvl. Specifically, defense-activated cells are concentrated in the anterior part of the VMHvl, which preferentially targets the periaqueductal gray (PAG). Thus, our study identified an essential neural substrate for active conspecific defense and expanded the function of the VMHvl.

Aggression is a crucial survival behavior: it is employed to defend territory, compete for food and mating opportunities, protect kin, and resolve disputes. Although widely differing in its behavioral expression, aggression is observed across many species. The neural substrates of aggression have been investigated for nearly a century and two highly conserved circuitries emerge as critical substrates for generating and modulating aggression. One circuitry centers on the medial hypothalamus. Activity of the medial hypothalamic cells closely correlates with attacks and can bi-directionally modulate aggressive behaviors. The other aggression-related circuit involves the mesolimbic dopamine cells. Dopaminergic antagonists are the most commonly used treatment for suppressing human aggression in psychotic patients. Animal studies support essential roles of dopaminergic signaling in the nucleus accumbens in assessing the reward value of aggression and reinforcing the aggressive behaviors. In this review, we will provide an overview regarding the functions of medial hypothalamus and dopaminergic system in mediating aggressive behaviors and the potential interactions between these two circuitries.

Aggression is a fundamental social behavior that is essential for competing for resources and protecting oneself and families in both males and females. As a result of natural selection, aggression is often displayed differentially between the sexes, typically at a higher level in males than females. Here, we highlight the behavioral differences between male and female aggression in rodents. We further outline the aggression circuits in males and females, and compare their differences at each circuit node. Lastly, we summarize our current understanding regarding the generation of sexually dimorphic aggression circuits during development and their maintenance during adulthood. In both cases, gonadal steroid hormones appear to play crucial roles in differentiating the circuits by impacting on the survival, morphology, and intrinsic properties of relevant cells. Many other factors, such as environment and experience, may also contribute to sex differences in aggression and remain to be investigated in future studies.

Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here, we report the development of genetically encoded GPCR-activation-based-DA (GRAB_DA) sensors that enable these measurements. In response to extracellular DA, GRAB_DA sensors exhibit large fluorescence increases (ΔF/F₀ ∼90%) with subcellular resolution, subsecond kinetics, nanomolar to submicromolar affinities, and excellent molecular specificity. GRAB_DA sensors can resolve a single-electrical-stimulus-evoked DA release in mouse brain slices and detect endogenous DA release in living flies, fish, and mice. In freely behaving mice, GRAB_DA sensors readily report optogenetically elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA signaling during Pavlovian conditioning or during sexual behaviors. Thus, GRAB_DA sensors enable spatiotemporally precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors.

Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the MPOA as key mediators of pup approach and retrieval. Reversible inactivation of MPOA^Esr1+cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOA^Esr1+cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOA^Esr1+cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors.