SUMMARY Sex hormones such as estrogen and testosterone are essential for sexually dimorphic behaviors in vertebrates. However, the hormone-activated molecular mechanisms that control the development and function of the underlying neural circuits remain poorly defined. We have identified numerous sexually dimorphic gene expression patterns in the adult mouse hypothalamus and amygdala. We find that adult sex hormones regulate these expression patterns in a sex-specific, regionally-restricted manner, suggesting that these genes regulate sex typical behaviors. Indeed, we find that mice with targeted disruptions of each of four of these genes (Brs3, Cckar, Irs4, Sytl4) exhibit extremely specific deficits in sex specific behaviors, with single genes controlling the pattern or extent of male sexual behavior, male aggression, maternal behavior, or female sexual behavior. Taken together, our findings demonstrate that various components of sexually dimorphic behaviors are governed by separable genetic programs.

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.

Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (

The medial preoptic area (mPOA) differs between males and females in nearly all species examined to date, including humans. Here, using fiber photometry recordings of Ca2+ transients in freely behaving mice, we show ramping activities in the mPOA that precede and correlate with sexually dimorphic display of male-typical mounting and female-typical pup retrieval. Strikingly, optogenetic stimulation of the mPOA elicits similar display of mounting and pup retrieval in both males and females. Furthermore, by means of recording, ablation, optogenetic activation, and inhibition, we show mPOA neurons expressing estrogen receptor alpha (Esr1) are essential for the sexually biased display of these behaviors. Together, these results underscore the shared layout of the brain that can mediate sex-specific behaviors in both male and female mice and provide an important functional frame to decode neural mechanisms governing sexually dimorphic behaviors in the future.

Dopamine (DA) and its D 2 receptor (R) are involved in cognition, reward processing, and drug addiction. However, their roles in sleep-wake regulation remain unclear. Herein we investigated the role of D 2 R in sleep-wake regulation by using D 2 R knock-out (KO) mice and pharmacological manipulation. Compared with WT mice, D 2 R KO mice exhibited a significant decrease in wakefulness, with a concomitant increase in non-rapid eye movement (non-REM, NREM) and REM sleep and a drastic decrease in the low-frequency (0.75-2 Hz) electroencephalogram delta power of NREM sleep, especially during the first 4 h after lights off. The KO mice had decreased mean episode duration and increased episode numbers of wake and NREM sleep, many stage transitions between wakefulness and NREM sleep during the dark period, suggesting the instability of the wake stage in these D 2 R KO mice. When the KO mice were subjected to a cage change or an intraperitoneal saline injection, the latency to sleep in the KO mice decreased to half of the level for WT mice. The D 2 R antagonist raclopride mimicked these effects in WT mice. When GBR12909, a dopamine transport inhibitor, was administered intraperitoneally, it induced wakefulness in WT mice in a dose-dependent manner, but its arousal effect was attenuated to one-third in the D 2 R KO mice. However, these 2 genotypes showed an identical response in terms of sleep rebound after 2, 4, and 6 h of sleep deprivation. These results indicate that D 2 R plays an essential role in the maintenance of wakefulness, but not in homeostatic regulation of NREM sleep.

Highlights d Neurons in l/vlPAG exhibit scratching behavior related to neural activities d Ablation of Tac1 + but not SST + neurons decreases itchinduced scratching behavior d Activation of Tac1 + neurons induces spontaneous scratching and grooming behaviors d l/vlPAG Tac1 + neurons modulate spinal itch processing via a RVM-dependent pathway

Highlights d The ipsi-and contralateral spinoparabrachial pathways are functionally distinct d The ipsilateral spinoparabrachial pathway mediates nocifensive behavior d Tacr1 + neurons in the PBN represent the major target of spinal projection d The PBN relays nociceptive information to the ILN via glutamatergic synapses

The aim of this study was to record gastric myoelectric activity using multichannel electrogastrography (EGG) and to determine if there are differences due to age, gender, body mass, and study location. In 61 normal subjects from four centers, fasting multichannel EGG was recorded for 1 h, followed by two 1-h postprandial recordings after a test meal. Variables assessed included dominant frequency (DF) and its power, percentage time in 2- to 4-cpm frequency, and percentage slow-wave coupling (%SWC). There were no significant differences in EGG parameters with respect to gender or age. Subjects with a BMI > 25 had a decrease in the absolute DF power but a similar increase in the postprandial DF power. Subjects with a BMI > 25 had a postprandial decrease in the %SWC compared to those with a BMI < 25. There was a decrease in postprandial %SWC in European/Asian centers compared to American centers. In conclusion, multichannel EGG provides assessment of electrical slow-wave coupling in addition to determining dominant frequency, power, and percentage normal rhythm. This multicenter study of normal subjects shows similar multichannel EGG values among different genders and ages. Body mass and ethnicity may impact on some of the EGG values.