Faculty Bibliography

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.

BACKGROUND:Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. METHODS:We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking. RESULTS:A selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens-a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat's inactive phase. CONCLUSIONS:REMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse.

The association between cause and effect is usually probabilistic. Memories triggered by ambiguous cues may be altered or biased into a more negative perception in psychiatric diseases. Understanding the formation and modulation of this probabilistic association is important for revealing the nature of aversive memory and alterations in brain diseases. We found that 50% conditioned and unconditioned stimuli (CS-US) association during Pavlovian fear conditioning results in reduced fear responses and neural spiking in the dorsomedial prefrontal cortex (dmPFC) due to enhanced inhibition from dmPFC parvalbumin (PV) neurons. Formation of probabilistic memory is associated with increased synaptic inputs to PV-neurons and requires activation of ventral hippocampus, which detects CS-US mismatch during conditioning. Stress prior to conditioning impairs the formation of probabilistic memory by abolishing PV-neuronal plasticity, while stress prior to memory retrieval reverts enhanced PV-neuron activity. In conclusion, PV-neurons tailor learned responses to fit brain state at the moment of retrieval.

BACKGROUND:N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. METHODS:By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. RESULTS:In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. CONCLUSIONS:We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

Conditioned inhibition is an important process to suppress learned responses for optimal adaptation, but its underlying biological mechanism is poorly understood. Here we used safety learning (SL)/fear discrimination after fear conditioning as a conditioned inhibition model because it demonstrates the essential properties of summation and retardation. Activity of the dorsomedial prefrontal cortex (dmPFC) parvalbumin (PV) neurons bidirectionally regulates spiking levels of dmPFC excitatory neurons and fear states. Responses to safety cues are increased in dopaminergic (DA) neurons in the ventral tegmental area (VTA) and in PV neurons in dmPFC after SL. Plasticity in the VTA is implicated, since SL requires activation of N-methyl-d-aspartate receptors. Furthermore, in a posttraumatic stress disorder model, impaired SL is associated with impaired potentiation of VTA DA neuron activity. Our results demonstrate a DA-dependent learning process that targets prefrontal inhibitory neurons for suppression of learned responses, and have implications for the pathogenesis and treatment of various psychiatric diseases.

Contexts play critical roles in many important aspects of an animal's routine functions, such as the interpretation of incoming signals and retrieved memories. The roles played by prefrontal cortex (PFC) neurons in the coding of contexts have been largely studied in relation to aversive stimuli (such as foot shock in conditioned fear). Whether PFC neurons may code contexts that mice encounter in everyday life, such as their home cage, is poorly understood. Here, we report the identification of a subpopulation of ventral medial PFC (vmPFC) neurons which change their spike rates when mice enter or leave their home cages. Both increase (ON units) and decrease (OFF units) in spike rate were observed, with about 2/3 of neurons showing decrease and 1/3 showing increase. These changes were evident whenever transitions occur from home cage to a different environment regardless of the novelty of the environments. In addition, changes in firing rate were not affected when mice entering a context where fear conditioning had taken place after contextual or auditory/cued fear conditioning. Furthermore, we found that the differential spike rates of ON and OFF units appear to allow mice to recognize that they are inside their home cages. Together, vmPFC neural spiking appears to enable the encoding of "home cage".