Methamphetamine (METH) abuse is associated with a spectrum of behavioral consequences, among which heightened aggression presents a significant challenge. However, the causal role of METH\'s impact in aggression and its target circuit mechanisms remains largely unknown. We established an acute METH exposure-aggression mouse model to investigate the role of ventral tegmental area (VTA) dopaminergic neurons and ventral medial hypothalamus VMH glutamatergic neuron. Our findings revealed that METH-induced VTA dopamine excitability activates the ventromedial hypothalamus (VMH) glutamatergic neurons, contributing to pathological aggression. Notably, we uncovered a dopaminergic transmission within the VTA-VMH circuit that exclusively functioned under METH influence. This dopaminergic pathway emerged as a potential key player in enabling dopamine-related pathological aggression, with heightened dopaminergic excitability implicated in various psychiatric symptoms. Also, the modulatory function of this pathway opens new possibilities for targeted therapeutic strategies for intervention to improve treatment in METH abuse and may have broader implications for addressing pathological aggression syndromes.

Good sleep quality is essential for maintaining the body\'s attention during wakefulness, which is easily affected by external factors such as an ambient temperature. However, the mechanism by which an ambient temperature influences sleep-wake behaviors remains unclear. The dorsomedial hypothalamus (DMH) has been reported to be involved in thermoregulation. It also receives projection from the preoptic area, which is an important region for sleep and energy homeostasis and the suprachiasmatic nucleus-a main control area of the clock rhythm. Therefore, we hypothesized that the DMH plays an important role in the regulation of sleep related to ambient temperatures. In this study, we found that cold exposure (24/20/16/12 °C) increased wakefulness and decreased non-rapid eye movement (NREM) sleep, while warm exposure (32/36/40/44 °C) increased NREM sleep and decreased wakefulness compared to 28 °C conditions in wild-type mice. Then, using non-specific and specific apoptosis, we found that lesions of whole DMH neurons and DMH γ-aminobutyric acid (GABA)-ergic neurons induced by caspase-3 virus aggravated the fluctuation of core body temperature after warm exposure and attenuated the change in sleep-wake behaviors during cold and warm exposure. However, chemogenetic activation or inhibition of DMH GABAergic neurons did not affect the sleep-wake cycle. Collectively, our findings reveal an essential role of DMH GABAergic neurons in the regulation of sleep-wake behaviors elicited by a change in ambient temperature.

Electroconvulsive seizure (ECS) therapy is highly effective in the treatment of several psychiatric disorders, including depression. Past studies have shown that the rodent model of ECS reveals the activation of multiple brain regions including the hypothalamus, suggesting that this method of brain stimulation broadly regulates central neuronal function, which results in peripheral function. The ventromedial nucleus of the hypothalamus (VMH) plays an important role in feeding and energy homeostasis. Our previous study showed that ECS increases the expression of anorexigenic factors in the VMH and has an anorexigenic effect in a mouse model. Since the VMH is also suggested to play a critical role in the peripheral lipid metabolism of white adipose tissue (WAT), we hypothesized that ECS alters lipid metabolism via activation of the VMH.
Here, we demonstrate that repeated ECS suppresses the fat mass of epididymal WAT and significantly increases the expression levels of lipolytic and brown adipose tissue markers such as Adrb3, Hsl/Lipe, and Ppargc1a. In the VMH, ECS increased the expression of multiple genes, notably Bdnf, Adcyap1, and Crhr2, which are not only anorexigenic factors but are also modulators of lipid metabolism. Furthermore, gold-thioglucose-induced hypothalamic lesions affecting the VMH abolished the effect of ECS on the WAT, indicating that hypothalamus activation is required for the phenotypic changes seen in the epididymal WAT.
Our data demonstrates a new effect of ECS on the lipid metabolism of WAT via induction of hypothalamic activity involving the VMH.

Neurokinin B (NKB) is critical for fertility in humans and stimulates gonadotrophin-releasing hormone/luteinising hormone (LH) secretion in several species, including sheep. There is increasing evidence that the actions of NKB in the retrochiasmatic area (RCh) contribute to the induction of the preovulatory LH surge in sheep. In the present study, we determined whether there are sex differences in the response to RCh administration of senktide, an agonist to the NKB receptor (neurokinin receptor-3 [NK3R]), and in NKB and NK3R expression in the RCh of sheep. To normalise endogenous hormone concentrations, animals were gonadectomised and given implants to mimic the pattern of ovarian steroids seen in the oestrous cycle. In females, senktide microimplants in the RCh produced an increase in LH concentrations that lasted for at least 8 hours after the start of treatment, whereas a much shorter increment (approximately 2 hours) was seen in males. We next collected tissue from gonadectomised lambs 18 hours after the insertion of oestradiol implants that produce an LH surge in female, but not male, sheep for immunohistochemical analysis of NKB and NK3R expression. As expected, there were more NKB-containing neurones in the arcuate nucleus of females than males. Interestingly, there was a similar sexual dimorphism in NK3R-containing neurones in the RCh, NKB-containing close contacts onto these RCh NK3R neurones, and overall NKB-positive fibres in this region. These data demonstrate that there are both functional and morphological sex differences in NKB-NK3R signalling in the RCh and raise the possibility that this dimorphism contributes to the sex-dependent ability of oestradiol to induce an LH surge in female sheep.

To analyze the long-term efficacy and cognitive effects of voltage-based deep brain stimulation (DBS) for drug-resistant essential tremor (ET).
Patients with drug-resistant ET and treated by voltage-based DBS of the ventral intermediate nucleus (VIM-DBS) were continuously enrolled. Seizure outcomes were assessed by blinded observers using the Tremor Rating Scale (TRS). The full-scale intelligence quotient, full-scale memory quotient, Hamilton Depression Scale, Hamilton Anxiety Scale, and Quality of Life in Essential Tremor Questionnaire were assessed as measures of cognitive function.
Eleven patients met the inclusion criteria, and two of them were excluded because of loss to follow-up. The patient follow-up times ranged from 48 to 66 months (median 51 months). TRS scores decreased by 60.4% and 46.0% at the 12- and 48-month follow-ups, respectively. Both changes were highly significant. During the follow-up period, the patients\' intelligence and memory had not significantly changed; depression, anxiety, and quality of life significantly improved. After long-term follow-up, the stimulation efficacy and quality of life gradually decreased, and the depression and anxiety levels increased.
For patients with drug-resistant ET, voltage-based DBS can provide acceptable benefits on tremor, cognitive function, and quality of life. However, the efficacy of VIM-DBS decreased over time.

The role of central juxtaposed with another zinc finger gene 1 (JAZF1) in glucose regulation remains unclear. Here, we activated mediobasal hypothalamus (MBH) JAZF1 in high-fat diet (HFD)-fed rats by an adenovirus expressing JAZF1 (Ad-JAZF1). We evaluated the changes in the hypothalamic insulin receptor (InsR)-PI3K-Akt-AMPK pathway and hepatic glucose production (HGP). To investigate the impact of MBH Ad-JAZF1 on HGP, we activated MBH JAZF1 in the presence or absence of ATP-dependent potassium (KATP ) channel inhibition, hepatic branch vagotomy (HVG), or an AMPK activator (AICAR). In HFD-fed rats, MBH Ad-JAZF1 decreased body weight and food intake, and inhibited HGP by increasing hepatic insulin signaling. Under insulin stimulation, MBH Ad-JAZF1 increased InsR and Akt phosphorylation, and phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) formation; however, AMPK phosphorylation was decreased in the hypothalamus. The positive effect of MBH JAZF1 on hepatic insulin signaling and HGP was prevented by treatment with a KATP channel inhibitor or HVG. The metabolic impact of hypothalamic JAZF1 was also blocked by MBH AICAR. Ad-JAZF1 treatment in SH-SY5Y cells resulted in an elevation of InsR and Akt phosphorylation following insulin stimulation. Our findings show that hypothalamic JAZF1 regulates HGP via the InsR-PI3K-Akt-AMPK pathway and KATP channels.

The tuberal hypothalamus is comprised of the dorsomedial, ventromedial, and arcuate nuclei, as well as parts of the lateral hypothalamic area, and it governs a wide range of physiologies. During neurogenesis, tuberal hypothalamic neurons are thought to be born in a dorsal-to-ventral and outside-in pattern, although the accuracy of this description has been questioned over the years. Moreover, the intrinsic factors that control the timing of neurogenesis in this region are poorly characterized. Proneural genes, including Achate-scute-like 1 (Ascl1) and Neurogenin 3 (Neurog3) are widely expressed in hypothalamic progenitors and contribute to lineage commitment and subtype-specific neuronal identifies, but the potential role of Neurogenin 2 (Neurog2) remains unexplored. Birthdating in male and female mice showed that tuberal hypothalamic neurogenesis begins as early as E9.5 in the lateral hypothalamic and arcuate and rapidly expands to dorsomedial and ventromedial neurons by E10.5, peaking throughout the region by E11.5. We confirmed an outside-in trend, except for neurons born at E9.5, and uncovered a rostrocaudal progression but did not confirm a dorsal-ventral patterning to tuberal hypothalamic neuronal birth. In the absence of Neurog2, neurogenesis stalls, with a significant reduction in early-born BrdU+ cells but no change at later time points. Further, the loss of Ascl1 yielded a similar delay in neuronal birth, suggesting that Ascl1 cannot rescue the loss of Neurog2 and that these proneural genes act independently in the tuberal hypothalamus. Together, our findings show that Neurog2 functions as a classical proneural gene to regulate the temporal progression of tuberal hypothalamic neurogenesis.SIGNIFICANCE STATEMENT Here, we investigated the general timing and pattern of neurogenesis within the tuberal hypothalamus. Our results confirmed an outside-in trend of neurogenesis and uncovered a rostrocaudal progression. We also showed that Neurog2 acts as a classical proneural gene and is responsible for regulating the birth of early-born neurons within the ventromedial hypothalamus, acting independently of Ascl1 In addition, we revealed a role for Neurog2 in cell fate specification and differentiation of ventromedial -specific neurons. Last, Neurog2 does not have cross-inhibitory effects on Neurog1, Neurog3, and Ascl1 These findings are the first to reveal a role for Neurog2 in hypothalamic development.

Even though several of RFamide peptides have been shown to modify memory and learning processes in different species, almost nothing is known regarding cognitive effects of recently discovered neuropeptide QRFP. Considering multiple physiological functions of QRFP, localization of QRFP-synthesizing neurons in the hypothalamus and its\' widely spread binding sites within the CNS, the present study was designed to investigate the possible role of QRFP in the consolidation of spatial memory. As target area for microinjection, the medial hypothalamic area, including dorsomedial (DMN) and ventromedial (VMN) nuclei, has been chosen. At first, the effects of two doses (200 ng and 400 ng) of QRFP were investigated in Morris water maze. After that receptor antagonist BIBP3226 (equimolar amount to the effective dose of neuropeptide) was applied to elucidate whether it can prevent effects of QRFP. To reveal possible changes in anxiety level, animals were tested in Elevated plus maze. The higher dose of QRFP (400 ng) improved short-term memory consolidation in Morris water maze. Pretreatment with antagonist BIBP3226 abolished cognitive effects of QRFP. The neuropeptide did not affect anxiety level of rats. This study provides unique evidence regarding the role of QRFP in the consolidation of memory and gives the basis for further investigations of neuropeptide\'s cognitive effects.

The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesis and release. Because neurokinin B (NKB) increases in the hypothalamus as puberty approaches, we considered it a candidate for such a role. An initial study investigated the acute effects of an NKB agonist, senktide, on the secretion of DYN from MBH tissues incubated in vitro. In other experiments, central injections of senktide were administered to animals for 4 days then MBHs were collected for assessment of DYN synthesis or for the in vitro secretion of both DYN and GnRH. Because insulin-like growth factor (IGF)-1 has been shown to play an important role at puberty, additional animals received central injections of this peptide for 4 days to assess NKB and DYN synthesis or the in vitro secretion of NKB. The results obtained show that senktide administration up-regulates the NKB receptor protein, at the same time as suppressing the DYN and its receptor. Senktide consistently suppressed DYN and elevated GnRH secretion in the same tissue incubates from both the acute and chronic studies. IGF-1 administration caused an increase in NKB protein, at the same time as decreasing DYN protein. Furthermore, the central administration of IGF-1 caused an increase in NKB release, an action blocked by the IGF-1 receptor blocker, JB-1. These results indicate that the IGF-1/NKB pathway contributes to suppressing the DYN inhibitory tone on prepubertal GnRH secretion and thus facilitates the puberty-related increase in the release of GnRH to accelerate the onset of puberty.

Dorsal raphe nucleus (DRN) neurons are reciprocally connected to the locus coeruleus (LC) and send neural pathways to the medial hypothalamus (MH). The aim of this work was to investigate whether the blockade of α1-, α2- or β-noradrenergic receptors in the DRN or the inactivation of noradrenergic neurons in the LC modify defensive behaviours organised by MH neurons. For this purpose, Wistar male rats received microinjections of WB4101, RX821002, propranolol (α1-, α2- and β-noradrenergic receptor antagonists, respectively) or physiological saline in the DRN, followed 10 min later by MH GABAA receptor blockade. Other groups of animals received DSP-4 (a noradrenergic neurotoxin), physiological saline or only a needle insertion (sham group) into the LC, and 5 days later, bicuculline or physiological saline was administered in the MH. In all these cases, after MH treatment, the frequency and duration of defensive responses were recorded over 15 min. An anterograde neural tract tracer was also deposited in the DRN. DRN neurons send pathways to lateral and dorsomedial hypothalamus. Blockade of α1- and β-noradrenergic receptors in the DRN decreased escape reactions elicited by bicuculline microinjections in the MH. In addition, a significant increase in anxiety-like behaviours was observed after the blockade of α2-noradrenergic receptors in the DRN. LC pretreatment with DSP-4 decreased both anxiety- and panic attack-like behaviours evoked by GABAA receptor blockade in the MH. In summary, the present findings suggest that the norepinephrine-mediated system modulates defensive reactions organised by MH neurons at least in part via noradrenergic receptors recruitment on DRN neurons.