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This study explores the behavioral effects of modulating CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus (PH). Utilizing a chemogenetic approach in mice, we discovered that the activation of CaMKII + neurons within the PH is associated with heightened locomotor activity, reduced social interaction, and impulsive behavior unrelated to anxiety or avoidance. These observed behaviors share a significant resemblance with characteristics commonly found in attention deficit and hyperactivity disorder (ADHD). Notably, treatment with clonidine, which is frequently prescribed for ADHD, effectively reduced impulsive behaviors in our mouse model. Our findings uncover the role of the PH that has not been previously explored and suggest a possible involvement of the PH in the manifestation of ADHD-like behaviors., (© 2024. The Author(s).)

The supramammillary nucleus (SuM) is a small region in the ventromedial posterior hypothalamus. The SuM has been relatively understudied with much of the prior focus being on its connection with septo-hippocampal circuitry. Thus, most studies conducted until the 21st century examined its role in hippocampal processes, such as theta rhythm and learning/memory. In recent years, the SuM has been "rediscovered" as a crucial hub for several behavioral and cognitive processes, including reward-seeking, exploration, and social memory. Additionally, it has been shown to play significant roles in hippocampal plasticity and adult neurogenesis. This review highlights findings from recent studies using cutting-edge systems neuroscience tools that have shed light on these fascinating roles for the SuM., (Copyright © 2023 the authors.)

The posterior hypothalamic area (PHa), including the supramammillary nucleus (SuM) and posterior hypothalamic nuclei, forms a crucial part of the ascending brainstem hippocampal synchronizing pathway, that is involved in the frequency programming and modulation of rhythmic theta activity generated in limbic structures. Recent investigations show that in addition to being a modulator of limbic theta activity, the PHa is capable of producing well-synchronized local theta field potentials by itself. The purpose of this study was to examine the ability of the PHa to generate theta field potentials and accompanying cell discharges in response to glutamatergic stimulation under both in vitro and in vivo conditions. The second objective was to examine the electrophysiological properties of neurons located in the SuM and posterior hypothalamic nuclei. Extracellular in vivo and in vitro as well as intracellular in vitro experiments revealed that glutamatergic stimulation of PHa with kainic acid induces well-synchronized local theta field oscillations in both the supramammillary and posterior hypothalamic nuclei. Furthermore, the glutamatergic PHa theta rhythm recorded extracellularly was accompanied by the activity of specific subtypes of theta-related neurons. We identify, for the first time, a subpopulation of supramammillary and posterior hypothalamic neurons that express clear subthreshold membrane potential oscillations in the theta frequency range., (© 2023 Wiley Periodicals LLC.)

Methamphetamine (METH) is an addictive drug that threatens human health. The supramammillary nucleus (SuM) and its neural circuits play key roles in the regulation of spatial memory retrieval, and hippocampal contextual or social memory. Melatonin (MLT), a pineal hormone, can regulate hypothalamic-neurohypophysial activity. Our previous study showed that MLT attenuates METH-induced locomotor sensitization. However, whether MLT regulates SuM function and participates in METH-induced contextual memory retrieval remains unclear. Using a mouse model of METH-conditioned place preference (CPP) and sensitization, we found that METH activated c-Fos expression and elevated calcium (Ca²⁺) levels in SuM neurons. Chemogenetic inhibition of SuM attenuates CPP and sensitization. Pretreatment with MLT decreased c-Fos expression and Ca 2+ levels in the SuM and reversed METH-induced addictive behavior, effects that were blocked with the selective MT 2 receptors antagonist 4P-PDOT and the MT 1 receptors antagonist S26131. Furthermore, MLT reduced SuM synaptic plasticity, glutamate (Glu) release, and neuronal oscillations caused by METH, which were blocked by 4P-PDOT. In conclusion, our data revealed that MLT regulates neuronal synaptic plasticity in the SuM, likely through the MLT receptors (MTs), and plays a role in modulating METH-addictive behavior., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats., Competing Interests: WW, PS, ML, AT, BT, MC, PK, FR, SJ, MS, SM, MC, AS, NC, TW, JK, AA none, (© 2021, Wang et al.)

Locomotor speed is a basic input used to calculate one’s position, but where this signal comes from is unclear. We identified neurons in the supramammillary nucleus (SuM) of the rodent hypothalamus that were highly correlated with future locomotor speed and reliably drove locomotion when activated. Robust locomotion control was specifically identified in Tac1 (substance P)–expressing (SuM Tac1+ ) neurons, the activation of which selectively controlled the activity of speed-modulated hippocampal neurons. By contrast, Tac1 -deficient (SuM Tac1− ) cells weakly regulated locomotion but potently controlled the spike timing of hippocampal neurons and were sufficient to entrain local network oscillations. These findings emphasize that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a manner that may support spatial navigation.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy- N , N -di- n -propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N -methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Theta rhythm recorded as an extracellular synchronous field potential is generated in a number of brain sites including the hippocampus. The physiological occurrence of hippocampal theta rhythm is associated with the activation of a number of structures forming the ascending brainstem-hippocampal synchronizing pathway. Experimental evidence indicates that the supramammillary nucleus and posterior hypothalamic nuclei, considered as the posterior hypothalamic area, comprise a critical node of this ascending pathway. The posterior hypothalamic area plays an important role in movement control, place-learning, memory processing, emotion and arousal. In the light of multiplicity of functions of the posterior hypothalamic area and the influence of theta field oscillations on a number of neural processes, it is the authors' intent to summarize the data concerning the involvement of the supramammillary nucleus and posterior hypothalamic nuclei in the modulation of limbic theta rhythmicity as well as the ability of these brain structures to independently generate theta rhythmicity., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Rhythmical slow activity (theta) was mapped in the hypothalamic region in freely moving cats. We recorded well synchronized and high amplitude theta rhythm in the medial part of the hypothalamus posterior area. The EEG recordings made from lateral part of this hypothalamic region contained only irregular activity. These findings support earlier observations concerning the topography of hippocampal formation desynchrony and synchrony system. The observations of the present study also suggest that the hypothalamus posterior area is actively involved in the mechanisms responsible for generating theta oscillations in the cat.

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuM VGLUT2+ ::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuM VGLUT2+ ::POA neurons have extensive arborizations. SuM VGLUT2+ ::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuM VGLUT2+ ::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuM VGLUT2+ ::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuM VGLUT2+ ::POA population drove aversion but not anxiety like behaviors. Activation of SuM VGLUT2+ ::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuM VGLUT2+ ::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuM VGAT+ ) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors., Competing Interests: AE, SH, MV, AC, HS, AL, IN, TF, AK, MB, AN No competing interests declared, (© 2023, Escobedo et al.)

Animal studies have shown that pregnancy is associated with neural adaptations that promote maternal care. The hypothalamus represents a central structure of the mammalian maternal brain and hormonal priming of specific hypothalamic nuclei plays a key role in the induction and expression of maternal behavior. In humans, we have previously demonstrated that becoming a mother involves changes in grey matter anatomy, primarily in association areas of the cerebral cortex. In the current study, we investigated whether pregnancy renders anatomical changes in the hypothalamus. Using an advanced delineation technique, five hypothalamic substructures were defined in longitudinal MRI scans of 107 women extracted from two prospective pre-conception cohort studies, including 50 women who were scanned before and after pregnancy and 57 nulliparous control women scanned at a similar time interval. We showed that becoming a mother is associated with volume reductions in the anterior-superior, superior tuberal and posterior hypothalamus. In addition, these structural changes related to hormonal levels during pregnancy and specific aspects of self-reported maternal behavior in late pregnancy, including maternal-fetal attachment and nesting behavior. These findings show that pregnancy leads to changes in hypothalamic anatomy and suggest that these contribute to the development of maternal behavior in humans, supporting the conservation of key aspects of maternal brain circuitry and their role in maternal behavior across species., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oxytocin plays an important role in modulating social recognition memory. However, the direct implication of oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) and their downstream hypothalamic targets in regulating short- and long-term forms of social recognition memory has not been fully investigated. In this study, we employed a chemogenetic approach to target the activity of PVH oxytocin neurons in male rats and found that specific silencing of this neuronal population led to an impairment in short- and long-term social recognition memory. We combined viral-mediated fluorescent labeling of oxytocin neurons with immunohistochemical techniques and identified the supramammillary nucleus (SuM) of the hypothalamus as a target of PVH oxytocinergic axonal projections in rats. We used multiplex fluorescence in situ hybridization to label oxytocin receptors in the SuM and determined that they are predominantly expressed in glutamatergic neurons, including those that project to the CA2 region of the hippocampus. Finally, we used a highly selective oxytocin receptor antagonist in the SuM to examine the involvement of oxytocin signaling in modulating short- and long-term social recognition memory and found that it is necessary for the formation of both. This study discovered a previously undescribed role for the SuM in regulating social recognition memory via oxytocin signaling and reinforced the specific role of PVH oxytocin neurons in regulating this form of memory., (© 2023. The Author(s).)

The ventral posterior hypothalamus (VPH) is an anatomically complex brain region implicated in arousal, reproduction, energy balance, and memory processing. However, neuronal cell type diversity within the VPH is poorly understood, an impediment to deconstructing the roles of distinct VPH circuits in physiology and behavior. To address this question, we employed a droplet-based single-cell RNA sequencing (scRNA-seq) approach to systematically classify molecularly distinct cell populations in the mouse VPH. Analysis of >16,000 single cells revealed 20 neuronal and 18 non-neuronal cell populations, defined by suites of discriminatory markers. We validated differentially expressed genes in selected neuronal populations through fluorescence in situ hybridization (FISH). Focusing on the mammillary bodies (MB), we discovered transcriptionally-distinct clusters that exhibit neuroanatomical parcellation within MB subdivisions and topographic projections to the thalamus. This single-cell transcriptomic atlas of VPH cell types provides a resource for interrogating the circuit-level mechanisms underlying the diverse functions of VPH circuits., Competing Interests: LM, WF, KS, LW, EB, PR, AJ No competing interests declared, MB Affiliated with Bristol-Myers Squibb. The author has no financial interests to declare., (© 2020, Mickelsen et al.)

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.

Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Guanylyl cyclase C (GUCY2C) is the afferent central receptor in the gut-brain endocrine axis regulated by the anorexigenic intestinal hormone uroguanylin. GUCY2C mRNA and protein are produced in the hypothalamus, a major center regulating appetite and metabolic homeostasis. Further, GUCY2C mRNA and protein are expressed in the ventral midbrain, a principal structure regulating hedonic reward from behaviors including eating. While GUCY2C is expressed in hypothalamus and midbrain, its precise neuroanatomical organization and relationship with circuits regulating satiety remain unknown. Here, we reveal that hypothalamic GUCY2C mRNA is confined to the ventral premammillary nucleus (PMV), while in midbrain it is produced by neurons in the ventral tegmental area (VTA) and substantia nigra (SN). GUCY2C in the PMV is produced by 46% of neurons expressing anorexigenic leptin receptors, while in the VTA/SN it is produced in most tyrosine hydroxylase-immunoreactive neurons. In contrast to mRNA, GUCY2C protein is widely distributed throughout the brain in canonical sites of PMV and VTA/SN axonal projections. Selective stereotaxic ablation of PMV or VTA/SN neurons eliminated GUCY2C only in their respective canonical projection sites. Conversely, specific anterograde tracer analyses of PMV or VTA/SN neurons confirmed distinct GUCY2C-immunoreactive axons projecting to those canonical locations. Together, these findings reveal two discrete neuronal circuits expressing GUCY2C originating in the PMV in the hypothalamus and in the VTA/SN in midbrain, which separately project to other sites throughout the brain. They suggest a structural basis for a role for the GUCY2C-uroguanylin gut-brain endocrine axis in regulating homeostatic and behavioral components contributing to satiety.

Injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHAL) into the rat rostral and caudal supramammillary nucleus (SUM) provided expected patterns of projections into the hippocampus and the septal region. In addition, unexpectedly intense projections were observed into the claustrum defined by parvalbumin expression. Injections of the retrograde tracer fluorogold (FG) into the hippocampus and the region of the claustrum showed that the cells of origin of these projections distributed similarly within the borders of the SUM. The SUM is usually involved in control of hippocampal theta activity, but the observation of intense projections into the claustrum indicates that it may also influence isocortical processes. Therefore, the SUM may coordinate sensory processing in the isocortex with memory formation in the hippocampus., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Neurons containing melanin-concentrating hormone (MCH) in the posterior lateral hypothalamus play an integral role in rapid eye movement sleep (REMs) regulation. As MCH neurons also contain a variety of other neuropeptides [e.g., cocaine- and amphetamine-regulated transcript (CART) and nesfatin-1] and neurotransmitters (e.g., glutamate), the specific neurotransmitter responsible for REMs regulation is not known. We hypothesized that glutamate, the primary fast-acting neurotransmitter in MCH neurons, is necessary for REMs regulation. To test this hypothesis, we deleted vesicular glutamate transporter (Vglut2; necessary for synaptic release of glutamate) specifically from MCH neurons by crossing MCH-Cre mice (expressing Cre recombinase in MCH neurons) with Vglut2 flox/flox mice (expressing LoxP-modified alleles of Vglut2), and studied the amounts, architecture and diurnal variation of sleep-wake states during baseline conditions. We then activated the MCH neurons lacking glutamate neurotransmission using chemogenetic methods and tested whether these MCH neurons still promoted REMs. Our results indicate that glutamate in MCH neurons contributes to normal diurnal variability of REMs by regulating the levels of REMs during the dark period, but MCH neurons can promote REMs even in the absence of glutamate.

Introduction: Aggressive disorders, in patients with intellectual disability, are satisfactorily managed with an educational, psychological, and pharmacological approach. Posterior hypothalamic region deep brain stimulation emerged in the last two decades as a promising treatment for patients with severe aggressive disorders. However, limited experiences are reported in the literature., Methods: A systematic review was performed following PRISMA guidelines and recommendations by querying PubMed and Embase on August 24th, 2022, with the ensuing string parameters: ([deep brain stimulation] OR [DBS]) AND ([aggressiv*] OR disruptive). Cochrane Library, DynaMed, and ClinicalTrials.gov were consulted using the combination of keywords "deep brain stimulation" and "aggressive" or "aggression". The clinical outcome at the last follow-up and the rate of complications were considered primary and secondary outcomes of interest., Results: The initial search identified 1,080 records, but only 10 studies met the inclusion criteria and were considered. The analysis of clinical outcome and complications was therefore performed on a total of 60 patients. Quality of all selected studies was classified as high, but one. Mean Overt Aggression Scale (OAS) improvement was 68%, while Inventory for Client Agency Planning (ICAP) improvement ranged between 38.3% and 80%. Complications occurred in 4 patients (6.7%)., Conclusion: Posterior hypothalamic region deep brain stimulation may be considered a valuable option for patients with severe aggression disorders and ID. This review can represent a mainstay for those who will be engaged in the surgical treatment of these patients., (© 2024 S. Karger AG, Basel.)

Depression and cardiovascular disease are both augmented by daily life stress. Yet, the biological mechanisms that translate psychological stress into affective and physiological outcomes are unknown. Previously, we demonstrated that stimulation of the ventromedial prefrontal cortex (vmPFC) has sexually divergent outcomes on behavior and physiology. Importantly, the vmPFC does not innervate the brain regions that initiate autonomic or neuroendocrine stress responses; thus, we hypothesized that intermediate synapses integrate cortical information to regulate stress responding. The posterior hypothalamus (PH) directly innervates stress-effector regions and receives substantial innervation from the vmPFC. In the current studies, circuit-specific approaches examined whether vmPFC synapses in the PH coordinate stress responding. Here we tested the effects of optogenetic vmPFC-PH circuit stimulation in male and female rats on social and motivational behaviors as well as physiological stress responses. Additionally, an intersectional genetic approach was used to knock down synaptobrevin in PH-projecting vmPFC neurons. Our collective results indicate that male vmPFC-PH circuitry promotes positive motivational valence and is both sufficient and necessary to reduce sympathetic-mediated stress responses. In females, the vmPFC-PH circuit does not affect social or preference behaviors but is sufficient and necessary to elevate neuroendocrine stress responses. Altogether, these data suggest cortical regulation of stress reactivity and behavior is mediated, in part, by projections to the hypothalamus that function in a sex-specific manner., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The supramammillary nucleus (SuMN) exerts influences on a wide range of brain functions including feeding and feeding-independent fuel metabolism. However, which specific neuronal type(s) within the SuMN manifest this influence has not been delineated. This study investigated the effect of SuMN tyrosine hydroxylase (TH) (rate-limiting enzyme in dopamine synthesis) knockdown (THx) on peripheral fuel metabolism., Methods: SuMN-THx was accomplished using a virus-mediated shRNA to locally knockdown TH gene expression at the SuMN. The impact of SuMN-THx was examined over 35-72 days in rats least prone to developing metabolic syndrome (MS) - female Sprague-Dawley rats resistant to the obesogenic effect of high fat diet (HFDr) and fed regular chow (RC) - upon body weight/fat, feeding, glucose tolerance, and insulin sensitivity. The influence of HFD, gender, and long-term response of SuMN-THx was subsequently investigated in female HFDr rats fed HFD, male HFDr rats fed RC, and female HFD-sensitive rats fed RC over 1 year, respectively., Results: SuMN-THx induced obesity and glucose intolerance, elevated plasma leptin and triglycerides, increased hepatic mRNA levels of gluconeogenic, lipogenic, and pro-inflammatory genes, reduced white adipose fatty acid oxidation rate, and altered plasma corticosterone level and hepatic circadian gene expression. Moreover, SuMN-THx increased feeding during the natural resting/fasting period and altered ghrelin feeding response suggesting ghrelin resistance. This MS-inducing effect was enhanced by HFD feeding, similarly observed in male rats and persisted over 1 year., Discussion/conclusion: SuMN-THx induced long-term, gender-nonspecific, multiple pathophysiological changes leading to MS suggesting SuMN dopaminergic circuits communicating with other brain metabolism and behavior control centers modulate peripheral fuel metabolism., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Oxytocin (OXT) neurons project to various brain regions and its receptor expression is widely distributed. Although it has been reported that OXT administration affects cognitive function, it is unclear how endogenous OXT plays roles in cognitive function. The present study examined the role of endogenous OXT in mice cognitive function. OXT neurons were specifically activated by OXT neuron-specific excitatory Designer Receptors Exclusively Activated by Designer Drug expression system and following administration of clozapine-N-oxide (CNO). Object recognition memory was assessed with the novel object recognition task (NORT). Moreover, we observed the expression of c-Fos via immunohistochemical staining to confirm neuronal activity. In NORT, the novel object exploration time percentage significantly increased in CNO-treated mice. CNO-treated mice showed a significant increase in the number of c-Fos-positive cells in the supramammillary nucleus (SuM). In addition, we found that the OXT-positive fibers from paraventricular hypothalamic nucleus (PVN) were identified in the SuM. Furthermore, mice injected locally with CNO into the SuM to activate OXTergic axons projecting from the PVN to the SuM showed significantly increased percentage time of novel object exploration. Taken together, we proposed that object recognition memory in mice could be modulated by OXT neurons in the PVN projecting to the SuM., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Takahashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During navigation, hippocampal spatial maps are thought to interact with action-planning systems in other regions of cortex. We here report a key role for spike-time coordination in functional coupling of the medial prefrontal cortex (mPFC) to the hippocampus through the thalamic nucleus reuniens (NR). When rats perform a T-maze alternation task, spikes of neurons in mPFC and NR exhibit enhanced coordination to the CA1 theta rhythm before the choice point on the maze. A similar coordination to CA1 theta rhythm was observed in neurons of the supramammillary nucleus (SUM). Optogenetic silencing of SUM neurons reduced the temporal coordination in the mPFC-NR-CA1 circuit. Following SUM inactivation, trajectory representations were impaired in both NR and CA1, but not in mPFC, indicating a failure in transmission of action plans from mPFC to the hippocampus. The findings identify theta-frequency spike-time coordination as a mechanism for gating of information flow in the mPFC-NR-CA1 circuit., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuM vglut2 ) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuM vglut2 neurons. Inhibition of SuM vglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuM vglut2 neurons include a subpopulation containing both glutamate and GABA (SuM vgat/vglut2 ) and another also expressing nitric oxide synthase (SuM Nos1/Vglut2 ). Activation of SuM vgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuM vgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuM Nos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuM vglut2 neurons as a key node of the wake-sleep regulatory system.

Acute γ-aminobutyric acid (GABA) disinhibition in the posterior hypothalamus (PH) elicits defensive reactions that are considered anxiety- and panic attack-like behaviour, and these defensive reactions are followed by antinociception. Evidence indicates that the PH connects with the medial prefrontal cortex, particularly the anterior cingulate cortex (ACC), which seems to regulate these unconditioned fear-induced defensive responses. However, few studies have shown the participation of cortical regions in the control of behavioural and antinociceptive responses organised by diencephalic structures. It has been suggested that the glutamatergic system can mediate this cortical influence, as excitatory imbalance is believed to play a role in both defensive mechanisms. Thus, the aim of the present study was to investigate the involvement of ACC glutamatergic connections via blockade of local N-methyl-D-aspartate (NMDA) receptors to elaborate panic-like defensive behaviours and unconditioned fear-induced antinociception organised by PH neurons. Wistar rats were treated with microinjections of 0.9% NaCl or LY235959 (a selective NMDA receptor antagonist) in the ACC at different concentrations (2, 4 and 8 nmol/0.2μL), followed by GABA A receptor blockade in the PH. Defensive reactions were analysed for 20min, and the nociceptive threshold was then measured at 10-min intervals for 60min. Pretreatment of the ACC with LY235959 reduced both panic-like defensive behaviour and fear-induced antinociception evoked by PH GABAergic disinhibition. Our findings suggest that ACC NMDA receptor-signalled glutamatergic inputs play a relevant role in the organisation of anxiety- and panic attack-like behaviours and in fear-induced antinociception., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

The Transient Receptor Potential Vanilloid 1 (TRPV1) non-selective cation channel predominantly expressed in primary sensory neurons of the dorsal root and trigeminal ganglia mediates pain and neurogenic inflammation. TRPV1 mRNA and immunoreactivity were described in the central nervous system (CNS), but its precise expression pattern and function have not been clarified. Here we investigated Trpv1 mRNA expression in the mouse brain using ultrasensitive RNAScope in situ hybridization. The role of TRPV1 in anxiety, depression-like behaviors and memory functions was investigated by TRPV1-deficient mice and pharmacological antagonism by AMG9810. Trpv1 mRNA is selectively expressed in the supramammillary nucleus (SuM) co-localized with Vglut2 mRNA, but not with tyrosine hydroxylase immunopositivity demonstrating its presence in glutamatergic, but not dopaminergic neurons. TRPV1-deleted mice exhibited significantly reduced anxiety in the Light-Dark box and depression-like behaviors in the Forced Swim Test, but their performance in the Elevated Plus Maze as well as their spontaneous locomotor activity, memory and learning function in the Radial Arm Maze, Y-maze and Novel Object Recognition test were not different from WTs. AMG9810 (intraperitoneal injection 50 mg/kg) induced anti-depressant, but not anxiolytic effects. It is concluded that TRPV1 in the SuM might have functional relevance in mood regulation and TRPV1 antagonism could be a novel perspective for anti-depressant drugs., Competing Interests: Conflict of Interest All authors declare that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neurological surgery offers an opportunity to study brain functions, through either resection or implanted neuromodulation devices. Pathological aggressive behavior in patients with intellectual disability is a frequent condition that is difficult to treat using either supportive care or pharmacological therapy. The bulk of the laboratory studies performed throughout the 19th century enabled the formulation of hypotheses on brain circuits involved in the generation of emotions. Aggressive behavior was also studied extensively. Lesional radiofrequency surgery of the posterior hypothalamus, which peaked in the 1970s, was shown to be an effective therapy in many reported series. As with other surgical procedures for the treatment of psychiatric disorders, however, this therapy was abandoned for many reasons, including the risk of its misuse. Deep brain stimulation (DBS) offers the possibility of treating neurological and psychoaffective disorders through relatively reversible and adaptable therapy. Deep brain stimulation of the posterior hypothalamus was proposed and performed successfully in 2005 as a treatment for aggressive behavior. Other groups reported positive outcomes using target and parameter settings similar to those of the original study. Both the lesional and DBS approaches enabled researchers to explore the role of the posterior hypothalamus (or posterior hypothalamic area) in the autonomic and emotional systems.

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.

The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine. We also investigated the involvement of PH ionotropic glutamate receptors in the defensive behaviours and fear-induced antinociception by microinjecting NBQX (an AMPA/kainate receptor antagonist) and LY235959 (a NMDA receptor antagonist) into the PH. ACC pretreatment with lidocaine decreased the proaversive effect and antinociception evoked by GABA A receptor blockade in the PH, which suggests that there may be descending excitatory pathways from this cortical region to the PH. Microinjections of both NBQX and LY235959 into the PH also attenuated defensive and antinociceptive responses. This suggests that the blockade of AMPA/kainate and NMDA receptors reduces the activity of glutamatergic efferent pathways. Both inputs from the ACC to the PH and glutamatergic hypothalamic short links disinhibited by intra-hypothalamic GABA A receptors blockade are potentially implicated. Microinjection of a bidirectional neurotracer in the PH showed a Cg1-PH pathway and PH neuronal reciprocal connections with the periaqueductal grey matter. Microinjections of an antegrade neurotracer into the Cg1 showed axonal fibres and glutamatergic vesicle-immunoreactive terminal boutons surrounding both mediorostral-lateroposterior thalamic nucleus and PH neuronal perikarya. These data suggest a critical role played by ACC-PH glutamatergic pathways and AMPA/kainate and NMDA receptors in the panic attack-like reactions and antinociception organised by PH neurons., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Hypersecretion of luteinizing hormone (LH) is a common endocrinological finding of polycystic ovary syndrome (PCOS). This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of gonadotropin-releasing hormone (GnRH). We evaluated the relationship between the hypothalamic-pituitary-gonadal axis (HPG axis) and kisspeptin using a rat model of PCOS induced by letrozole. Letrozole pellets (0.4 mg/day) and control pellets were placed subcutaneously onto the backs of 3-week-old female Wistar rats. Body weight, vaginal opening and vaginal smear were checked daily. Blood and tissues of ovary, uterus and brain were collected at 12-weeks of age. An hypothalamic block was cut into anterior and posterior blocks, which included the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), respectively, in order to estimate hypothalamic kisspeptin expression in each area. The letrozole group showed a similar phenotype to human PCOS such as heavier body weight, heavier ovary, persistent anovulatory state, multiple enlarged follicles with no corpus luteum and higher LH and testosterone (T) levels compared to the control group. Kisspeptin mRNA expression in the posterior hypothalamic block including ARC was higher in the letrozole group than in the control group although its expression in the anterior hypothalamic block was similar between groups. These results suggest that enhanced KNDy neuron activity in ARC contributes to hypersecretion of LH in PCOS and might be a therapeutic target to rescue ovulatory disorder of PCOS in the future.

Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while β adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia.

A key mode of neuronal communication between distant brain regions is through excitatory synaptic transmission mediated by long-range glutamatergic projections emitted from principal neurons. The long-range glutamatergic projection normally forms numerous en passant excitatory synapses onto both principal neurons and interneurons along its path. Under physiological conditions, the monosynaptic excitatory drive onto postsynaptic principal neurons outweighs disynaptic feedforward inhibition, with the net effect of depolarizing principal neurons. In contrast with this conventional doctrine, here we report that a glutamatergic projection from the hypothalamic supramammillary nucleus (SuM) largely evades postsynaptic pyramidal neurons (PNs), but preferentially target interneurons in the hippocampal CA3 region to predominantly provide feedforward inhibition. Using viral-based retrograde and anterograde tracing and ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording in mice of either sex, we show that SuM projects sparsely to CA3 and provides minimal excitation onto CA3 PNs. Surprisingly, despite its sparse innervation, the SuM input inhibits all CA3 PNs along the transverse axis. Further, we find that SuM provides strong monosynaptic excitation onto CA3 parvalbumin-expressing interneurons evenly along the transverse axis, which likely mediates the SuM-driven feedforward inhibition. Together, our results demonstrate that a novel long-range glutamatergic pathway largely evades principal neurons, but rather preferentially innervates interneurons in a distant brain region to suppress principal neuron activity. Moreover, our findings reveal a new means by which SuM regulates hippocampal activity through SuM-to-CA3 circuit, independent of the previously focused projections from SuM to CA2 or dentate gyrus. SIGNIFICANCE STATEMENT The dominant mode of neuronal communication between brain regions is the excitatory synaptic transmission mediated by long-range glutamatergic projections, which form en passant excitatory synapses onto both pyramidal neurons and interneurons along its path. Under normal conditions, the excitation onto postsynaptic neurons outweighs feedforward inhibition, with the net effect of depolarization. In contrast with this conventional doctrine, here we report that a glutamatergic input from hypothalamic supramammillary nucleus (SuM) largely evades PNs but selectively targets interneurons to almost exclusively provide disynaptic feedforward inhibition onto hippocampal CA3 PNs. Thus, our findings reveal a novel subcortical-hippocampal circuit that enables SuM to regulate hippocampal activity via SuM-CA3 circuit, independent of its projections to CA2 or dentate gyrus., (Copyright © 2023 the authors.)

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network., Competing Interests: FG, JG, GE, AB, AL, AL, CT, WC, RM, EF, JB, PG, PA, HY, GI, NL, AL, CH No competing interests declared, (© 2023, Gouveia, Germann et al.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

New Findings: What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA-salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA-salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA-salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA-salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

Kowalczyk et al. (Hippocampus 2014; 24:7-20) were probably the first to conduct a systemic study of posterior hypothalamic area (PHa) theta rhythm in anesthetized rats. They demonstrated that local PHa theta field potentials were tail-pinch resistant and could be generated in urethane-anesthetized rats independently of ongoing hippocampal formation theta rhythm. These in vivo data were also confirmed in PHa slice preparations perfused with cholinergic agonist, carbachol. In the current experiments we extend our earlier observations concerning PHa theta rhythm. Specifically, PHa field potentials were analyzed in relation to the ongoing local cell firing repertoire. Single-unit discharge patterns of cells localized in the posterior hypothalamic and supramammillary nuclei were characterized according to the criteria that was developed previously to classify theta-related cells in the hippocampal formation. The present study demonstrated that in addition to the earlier described theta-related cells (theta-on, theta-off and gating cells) the PHa also contains cells discharging in a very regular manner, which were labelled "timing cells". This type of neuron has not been previously documented. We suggest that "timing cells" form a part of the ascending brainstem synchronizing pathway, provideing a regular rhythmic signal which facilitates the transduction of tonic discharges of cells localized in the brain stem into theta-frequency rhythmic discharges. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Data obtained in in vitro experiments and urethane anaesthetized animals have revealed that the mechanisms responsible for the generation of hippocampal cholinergic theta rhythm are specifically affected by the administration of broad spectrum gap junctions (GJs) blocker - carbenoxolone (CBX). The aim of this study was to examine the effect of GJs modulation on the production of posterior hypothalamic theta. Specifically, we were interested in evaluating whether CBX could attenuate the theta rhythm recorded from the supramammillary nucleus and posterior hypothalamic nuclei, in both in vitro and in vivo preparations. The data we obtained from in vitro and in vivo preparations demonstrated that the administration of CBX did not suppress cholinergically induced theta in posterior hypothalamic area (PHa) slices nor the theta rhythm observed in the PHa of urethane anaesthetized rats. Moreover, the application of trimethylamine, while very effective in the enhancement of hippocampal theta rhythm, did not produce any changes in theta oscillations observed in either in vitro or in vivo posterior hypothalamic area preparations. These data show that electrical coupling via GJs is not involved in theta rhythm generation in the PHa. Surprisingly, we observed a significant enhancement of theta activity in response to the carbenoxolone administration in both in vitro and in vivo PHa preparations. The theta rhythm enhancement detected in those experiments was attenuated by the application of spironolactone (mineralocorticoid receptors antagonist). We suggest that the observed excitatory effects of CBX on posterior hypothalamic oscillatory activity in the theta band could be mediated by mineralocorticoid receptors., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The theta rhythm discovered in the posterior hypothalamus area (PHa) differs from theta observed in the hippocampal formation. In comparison to hippocampal spontaneous theta, the theta recorded in the PHa is rarely registered, has lower amplitude, often disappears, and sometimes returns after a few minutes. These features indicate that spontaneous theta recorded in the PHa is not an appropriate experimental model to search for the correlation between PHa cell discharges and local field potential. In this paper we present standard experimental conditions necessary to record theta-related cells in the PHa in anesthetized rats. Three pharmacological agents were used in the experiments to induce PHa theta rhythm in urethanized rats: carbachol (CCH), carbenoxolone and kainic acid, which are potent enough to induce well-synchronized PHa theta. However, CCH was found to be the best pharmacological tool to induce PHa theta oscillations, due to its longest duration of action and lack of preliminary epileptogenic effects. It seems that CCH-induced theta can be the most suitable pharmacological model for experiments with the use of protocol of long-lasting recordings of PHa theta-related cell discharges., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A likely adaptive process mitigating the effects of chronic stress is the phenomenon of stress habituation, which frequently reduces multiple stress-evoked responses to the same (homotypic) stressor experienced repeatedly. The current studies investigated putative brain circuits that may coordinate the reduction of stress-related responses associated with stress habituation, a process that is inadequately understood. Initially, two rat premotor regions that respectively regulate neuroendocrine (medial parvicellular region of the paraventricular hypothalamic nucleus [PaMP]) and autonomic (rostral medullary raphe pallidus [RPa]) responses were targeted with distinguishable retrograde tracers. Two to 3 weeks later, injected animals underwent loud noise stress, and their brains were processed for fluorescent immunohistochemical detection of the tracers and the immediate early gene Fos. A rostral region of the posterior hypothalamic nucleus (rPH), and to a lesser extent, the median preoptic nucleus, exhibited the highest numbers of retrogradely labeled cells from both the RPa and PaMP that were colocalized with loud noise-induced Fos expression. Injections of an anterograde tracer in the rPH confirmed these connections and suggested that this region may contribute to the coordination of multiple stress-related responses. This hypothesis was partially tested by posterior hypothalamic injections of small volumes of muscimol, which disrupts normal synaptic functions, before acute and repeated loud noise or restraint exposures. In addition to significantly reduced corticosterone release in response to these two distinct stressors, rPH muscimol disrupted habituation to each stressor modality, suggesting a novel and important contribution of the rostral posterior hypothalamic nucleus in this category of adaptive processes. Significance statement: Habituation to stress is a process that possibly diminishes the detrimental health consequences of chronic stress by reducing the amplitude of many responses when the same challenging conditions are experienced repeatedly. Stress elicits a highly coordinated set of neuroendocrine, autonomic, and behavioral responses that are independently and relatively well defined; however, how the brain achieves coordination of these responses and their habituation-related declines is not well understood. The current studies provide some of the first anatomical and functional results suggesting that a specific region of the hypothalamus, the rostral posterior hypothalamic nucleus, targets multiple premotor regions and contributes to the regulation of acute neuroendocrine responses and their habituation to repeated stress., (Copyright © 2016 the authors 0270-6474/16/360795-11$15.00/0.)

In a rat model, the baroreceptor reflex can be assessed by graded infusions of either phenylephrine or sodium nitroprusside with continuous hemodynamic monitoring. Microinjection of the cholinergic agonist carbachol (CCh) into the posterior hypothalamic nucleus (PHN) evokes an increase in mean arterial pressure and a change in heart rate. Lower doses of CCh evoke only tachycardia, whereas middle and higher doses evoke a biphasic change in heart rate of tachycardia followed by bradycardia. The bradycardia following the microinjection of CCh into the PHN can be attenuated by the previous administration of the vasopressin V1 receptor antagonist [d(CH2 )5 Tyr(Me)] arginine vasopressin (AVPX). Circulating arginine vasopressin (AVP) has been shown to increase the sensitivity of the baroreceptor reflex by stimulating vasopressin V1 receptors in the area postrema. The attenuation by AVPX of the bradycardia that results following the high doses of CCh suggests that AVP is released into the circulation following stimulation of cholinergic systems within the PHN. Thus, microinjection of a high dose of CCh (11 nmol) into the PHN alters the sensitivity of the baroreceptor reflex by increasing peripheral levels of AVP., (© 2016 John Wiley & Sons Ltd.)

Background/aims: Photoperiod is a major environmental cue in temperate-zone birds which synchronizes breeding with the time of year that offers the optimal environment for offspring survival. Despite continued long photoperiods, these birds eventually become refractory to the stimulating photoperiod and their reproductive systems regress. In this study, we characterized the role of γ-aminobutyric acid (GABA)ergic neurotransmission in modulating the response of the premammillary nucleus (PMM) to a gonad stimulatory photoperiod and the onset of photorefractoriness., Methods and Results: Bilateral ablation of the PMM blocked the light-induced neuroendocrine response from occurring in photosensitive turkeys. Microarray analyses revealed an increase in GABAergic activity in the PMM of photorefractory birds as opposed to photosensitive ones, and this enhanced GABAergic activity appeared to inhibit the photoperiodic signal. Additionally, GABAA and GABAB receptors were expressed by dopamine-melatonin neurons in the PMM, and the administration of the GABA receptor agonist baclofen blocked the photoperiodic reproductive neuroendocrine responses., Conclusions: Consistent with the present findings, we propose that the long-sought-after mechanism underlying photorefractoriness is linked to the inhibitory actions of GABA. We suggest that (1) GABAergic interference with photoperiodic entrainment in the PMM initiates the photorefractory state and terminates the annual breeding season in temperate-zone birds, and (2) the PMM is a site of photoreception and photorefractoriness that controls the initiation and termination of avian reproductive seasonality., (© 2015 S. Karger AG, Basel.)

It is now well-established that the hippocampal CA2 region plays an important role in social recognition memory in adult mice. The CA2 is also important for the earliest social memories, including those that mice have for their mothers and littermates, which manifest themselves as a social preference for familiarity over novelty. The role of the CA2 in the development of social memory for recently encountered same-age conspecifics, that is, peers, has not been previously reported. Here, we used a direct social interaction test to characterize the emergence of novelty preference for peers during development and found that at the end of the second postnatal week, pups begin to significantly prefer novel over familiar peers. Using chemogenetic inhibition at this time, we showed that CA2 activity is necessary for the emergence of novelty preference and for the ability to distinguish never encountered from recently encountered peers. In adulthood, the CA2 region is known to integrate a large number of inputs from various sources, many of which participate in social recognition memory, but previous studies have not determined whether these afferents are present at adult levels by the end of the second postnatal week. To explore the development of CA2 inputs, we used immunolabeling and retrograde adenovirus circuit tracing and found that, by the end of the second postnatal week, the CA2 is innervated by many regions, including the dentate gyrus, supramammillary nucleus of the hypothalamus, the lateral entorhinal cortex, and the median raphe nucleus. Using retroviral labeling of postnatally generated granule cells in the dentate gyrus, we found that mossy fiber projections to the CA2 mature faster during development than those generated in adulthood. Together, our findings indicate that the CA2 is partially mature in afferent connectivity by the end of the second postnatal week, connections that likely facilitate the emergence of social recognition memory and preference for novel peers., (© 2022 Wiley Periodicals LLC.)

Objective: This study sought to characterize resting-state functional MRI (fMRI) connectivity patterns of the posterior hypothalamus (pHTH) and the nucleus basalis of Meynert (NBM) in surgical patients with mesial temporal lobe epilepsy (mTLE), and to investigate potential correlations between functional connectivity of these arousal regions and neurocognitive performance., Methods: The study evaluated resting-state fMRI in 60 patients with preoperative mTLE and in 95 healthy controls. The authors first conducted voxel-wise connectivity analyses seeded from the pHTH, combined anterior and tuberal hypothalamus (atHTH; i.e., the rest of the hypothalamus), and the NBM ipsilateral (ipsiNBM) and contralateral (contraNBM) to the epileptogenic zone. Based on these results, the authors included the pHTH, ipsiNBM, and frontoparietal neocortex in a network-based statistic (NBS) analysis to elucidate a network that best distinguishes patients from controls. The connections involving the pHTH and ipsiNBM from this network were included in age-corrected pairwise region of interest (ROI) analysis, along with connections between arousal structures, including the pHTH, ipsiNBM, and brainstem arousal regions. Finally, patient functional connectivity was correlated with clinical neurocognitive testing scores for IQ as well as attention and concentration tests., Results: The voxel-wise analysis demonstrated that the pHTH, when compared with the atHTH, showed more widespread functional connectivity decreases in surgical mTLE patients when compared with controls. It was also observed that the ipsiNBM, but not the contraNBM, showed decreased functional connectivity in mTLE. The NBS analysis uncovered a perturbed network of frontoparietal regions, the pHTH, and ipsiNBM that distinguishes patients from controls. Age-corrected ROI analysis revealed functional connectivity decreases between the pHTH and bilateral superior frontal gyri, medial orbitofrontal cortices, rostral anterior cingulate cortices, and inferior parietal cortices in mTLE when compared with controls. For the ipsiNBM, there was reduced connectivity with bilateral medial orbitofrontal and rostral anterior cingulate cortices. Age-corrected ROI analysis also demonstrated upstream connectivity decreases from controls between the pHTH and the brainstem arousal regions, cuneiform/subcuneiform (CSC) nuclei, and ventral tegmental area, as well as the ipsiNBM and CSC nuclei. Reduced functional connectivity was also detected between the pHTH and ipsiNBM. Lastly, neurocognitive test scores for attention and concentration were found to be positively correlated with the functional connectivity between the pHTH and ipsiNBM, suggesting worse performance associated with connectivity perturbations., Conclusions: This study demonstrated perturbed resting-state functional connectivity of arousal regions in surgical mTLE and is one of the first investigations to demonstrate decreased functional connectivity of the pHTH with frontoparietal regions and other arousal regions. Connectivity disturbances in arousal regions may contribute to neurocognitive deficits in surgical mTLE patients.

Purpose: Hypothalamic obesity (HO) is a complication associated with craniopharyngioma (CP). Attempts have been made to perioperatively predict the development of this complication, which can be severe and difficult to treat., Methods: Patients who underwent first transsphenoidal surgical resection in a single center between February 2005 and March 2019 were screened; those who have had prior surgery or radiation, were aged below 18 years, or did not have follow up body mass index (BMI) after surgery were excluded. Primary end point was BMI within 2 years post-surgery. Hypothalamic involvement (HI) was graded based on preoperative and postoperative imaging with regards to anterior, posterior, left and right involvement. Data on baseline demographics, pre-operative and post-operative MRI, and endocrine function were collected., Results: 45 patients met the inclusion and exclusion criteria. Most patients in our cohort underwent gross total resection (n = 35 patients). 13 patients were from no HI or anterior HI only group and 22 patients were classified as both anterior (ant) and posterior (post) HI group. There was no significant difference between the two groups in the gross total, subtotal or near total resection. Pre-operative BMI and post-operative BMI were significantly higher in patients who had ant and post HI on pre-operative MRI (p < 0.05 and p < 0.01, respectively). Similarly, post-operative BMI at 13-24 months was also significantly higher in the ant and post HI group on post-op MRI (p < 0.01). There was no significant difference between the two groups in terms of baseline adrenal insufficiency, thyroid insufficiency, gonadal insufficiency, IGF-1 levels, hyperprolactinemia, and diabetes insipidus. Diabetes insipidus was more common following surgery among those who had anterior and posterior involvement on pre-operative MRI (p < 0.05)., Conclusions: HO appears to be predetermined by tumor involvement in the posterior hypothalamus observed on pre-operative MRI. Posterior HI on pre-operative MRI was also associated with the development of diabetes insipidus after surgery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)