Posterior Hypothalamic Nucleus Research Articles

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Functional relationships of the cerebral cortex with subcortical structures in emotionally stressful conditions

Multidirectional and stable changes in phase shifts and cross-correlation coefficients of the cortical and subcortical stress rhythms occur under conditions of repeated irregular photostimulation, especially in the initial periods. Thus, cross-correlation functional connections, characterized by changes in the spatio-temporal relationships of the brain structures (posterior nuclei of the hypothalamus, reticular formation, and visual projection zones of the cerebral cortex), can be one of the indicators of the formation of stress. By using the parameters mentioned above, we can solve many issues related to the central mechanisms of stress. Our results show that functional connections between the cortical projection area and subcortical structures decrease under stress conditions, while connections between subcortical structures increase. We furthermore found that these EEG changes correlated with autonomic reactions in animals. Thus, these changes may lie based on central mechanisms of stress, and the results of changes in the EEG activity of the cerebral cortex and the cross-correlation parameters in the posterior nuclei of the hypothalamus and the reticular formation may allow preventive measures to be taken to affect these structures to reduce emotional stress.

CFOS as a biomarker of activity maturation in the hippocampal formation.

We explored the potential for cFOS expression as a marker of functional development of "resting-state" waking activity in the extended network of the hippocampus and entorhinal cortex. We examined sleeping and awake mice at (P)ostnatal days 5, 9, 13, and 17 as well as in adulthood. We find that cFOS expression is state-dependent even at 5 days old, with reliable staining occurring only in the awake mice. Even during waking, cFOS expression was rare and weak at P5. The septal nuclei, entorhinal cortex layer (L)2, and anterodorsal thalamus were exceptional in that they had robust cFOS expression at P5 that was similar to or greater than in adulthood. Significant P5 expression was also observed in the dentate gyrus, entorhinal cortex L6, postsubiculum L4-6, ventral subiculum, supramammillary nucleus, and posterior hypothalamic nucleus. The expression in these regions grew stronger with age, and the expression in new regions was added progressively at P9 and P13 by which point the overall expression pattern in many regions was qualitatively similar to the adult. Six regions-CA1, dorsal subiculum, postsubiculum L2-3, reuniens nucleus, and perirhinal and postrhinal cortices-were very late developing, mostly achieving adult levels only after P17. Our findings support a number of developmental principles. First, early spontaneous activity patterns induced by muscle twitches during sleep do not induce robust cFOS expression in the extended hippocampal network. Second, the development of cFOS expression follows the progressive activation along the trisynaptic circuit, rather than birth date or cellular maturation. Third, we reveal components of the egocentric head-direction and theta-rhythm circuits as the earliest cFOS active circuits in the forebrain. Our results suggest that cFOS staining may provide a reliable and sensitive biomarker for hippocampal formation activity development, particularly in regard to the attainment of a normal waking state and synchronizing rhythms such as theta and gamma.

Posterior hypothalamic theta rhythm: Electrophysiological basis and involvement of glutamatergic receptors.

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.

Neuroanatomical characterization of the G protein-coupled receptor activity evoked by galanin-related ligands

Galanin neuropeptide is distributed throughout the mammalian nervous system modulating a plethora of diverse physiological functions, including nociception, cognition and neuroendocrine regulation. The regulation of the galaninergic system is an interesting approach for the treatment of different diseases associated to those systems. Nevertheless, the pharmacological selectivity and activities of some galanin receptor (GalR) ligands are still in discussion and seem to depend on the dose, the receptor subtype and the second messengers to which they are coupled at different brain areas. The activity of different GalR ligands on Gi/o proteins, was evaluated by the guanosine 5′-(γ-[35S]thio)triphosphate ([35S]GTPγS) autoradiography in vitro assay applied to rat brain tissue slices in the presence of galanin, M15, M35, M40, gal(2−11) or galnon. The enhancement of the [35S]GTPγS binding induced by the chimerical peptides M15, M35 and M40 was similar to that produced by Gal in those brain areas showing the highest stimulations, such as dorsal part of the olfactory nucleus and ventral subiculum. In contrast to these peptides, using gal(2−11) no effect was measured on Gi/o protein coupling in areas of the rat brain with high GalR1 density such as posterior hypothalamic nucleus and amygdala, indicating low selectivity for GalR1 receptors. The effects evoked by the non-peptide ligand, galnon, were different from those induced by galanin, behaving as agonist or antagonist depending on the brain area, but the stimulations were always blocked by M35. Thus, the activity of most used GalR ligands on Gi/o protein mediated signalling is complex and depends on the brain area. More selective and potent GalR ligands are necessary to develop new treatments aimed to modulate the galaninergic system.

Eye pupil – a window into central autonomic regulation via emotional/cognitive processing

If the eyes are windows into the soul, then the pupils represent at least the gateway to the brain and can provide a unique insight into the human mind from several aspects. The changes in the pupil size primarily mediated by different lighting conditions are controlled by the autonomic nervous system regulated predominantly at the subcortical level. Specifically, parasympathetically-linked pupillary constriction is under the Edinger-Westphal nucleus control and sympathetically-mediated pupillary dilation is regulated from the posterior hypothalamic nuclei. However, the changes in the pupil size can be observed at resting state even under constant lighting, these pupillary changes are mediated by global arousal level as well as by various cognitive factors. In this context, autonomic pathways modulating changes in the pupil size in response to the different light levels can be influenced by multiple central descending inputs driving pupillary changes under steady lighting conditions. Moreover, as the pupillary response is involved in emotional (task-evoked pupillary dilation as an index of emotional arousal) and cognitive (task-evoked pupillary dilation as an index of cognitive workload) stimulation, it can be used to detect the impact of mutual subcortical and cortical structures (i.e. overlapping brain structures included in autonomic, emotional and cognitive regulation) on the pupillary innervation system. Thus, complex understanding of the baseline pupil size´ and pupillary dynamics´ mechanisms may provide an important insight into the central nervous system functioning pointing to the pupillometry as a promising tool in the clinical application.

Eye pupil – a window into central autonomic regulation via emotional/cognitive processing

If the eyes are windows into the soul, then the pupils represent at least the gateway to the brain and can provide a unique insight into the human mind from several aspects. The changes in the pupil size primarily mediated by different lighting conditions are controlled by the autonomic nervous system regulated predominantly at the subcortical level. Specifically, parasympathetically-linked pupillary constriction is under the Edinger-Westphal nucleus control and sympathetically-mediated pupillary dilation is regulated from the posterior hypothalamic nuclei. However, the changes in the pupil size can be observed at resting state even under constant lighting, these pupillary changes are mediated by global arousal level as well as by various cognitive factors. In this context, autonomic pathways modulating changes in the pupil size in response to the different light levels can be influenced by multiple central descending inputs driving pupillary changes under steady lighting conditions. Moreover, as the pupillary response is involved in emotional (task-evoked pupillary dilation as an index of emotional arousal) and cognitive (task-evoked pupillary dilation as an index of cognitive workload) stimulation, it can be used to detect the impact of mutual subcortical and cortical structures (i.e. overlapping brain structures included in autonomic, emotional and cognitive regulation) on the pupillary innervation system. Thus, complex understanding of the baseline pupil size´ and pupillary dynamics´ mechanisms may provide an important insight into the central nervous system functioning pointing to the pupillometry as a promising tool in the clinical application.

Oxytocinergic cells of the posterior hypothalamic paraventricular nucleus participate in the food entrained clock

The mechanisms underlying food anticipatory activity are still poorly understood. Here we explored the role of oxytocin (OT) and the protein c-Fos in the supraoptic nucleus (SON), medial (PVNm) and posterior (PVNp) regions of the paraventricular hypothalamic nucleus. Adult rats were assigned to one of four groups: scheduled restricted feeding (RF), ad libitum (AL), fasting after restricted feeding (RF-F), to explore the possible persistence of oscillations, or ad libitum fasted (AL-F). In the SON and in the PVNm, OT cells were c-Fos positive after food intake; in contrast, OT cells in the PVNp showed c-Fos activation in anticipation to food access, which persisted in RF-F subjects. We conclude that OT and non-OT cells of the SON and PVNm may play a role as recipients of the entraining signal provided by food intake, whereas those of the PVNp which contain motor preautonomic cells that project to peripheral organs, may be involved in the hormonal and metabolic anticipatory changes in preparation for food presentation and thus, may be part of a link between central and peripheral oscillators. In addition, due to their persistent activation they may participate in the neuronal network for the clock mechanism that leads to food entrainment.

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats.

Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.

Whole-brain mapping of afferent projections to the suprachiasmatic nucleus of the tree shrew

The suprachiasmatic nucleus (SCN) is essential for the neural control of mammalian circadian timing system. The circadian activity of the SCN is modulated by its afferent projections. In the present study, we examine neuroanatomical characteristics and afferent projections of the SCN in the tree shrew (Tupaia belangeri chinensis) using immunocytochemistry and retrograde tracer Fluoro-Gold (FG). Distribution of the vasoactive intestinal peptide was present in the SCN from rostral to caudal, especially concentrated in its ventral part. FG-labeled neurons were observed in the lateral septal nucleus, septofimbrial nucleus, paraventricular thalamic nucleus, posterior hypothalamic nucleus, posterior complex of the thalamus, ventral subiculum, rostral linear nucleus of the raphe, periaqueductal gray, mesencephalic reticular formation, dorsal raphe nucleus, pedunculopontine tegmental nucleus, medial parabrachial nucleus, locus coeruleus, parvicellular reticular nucleus, intermediate reticular nucleus, and ventrolateral reticular nucleus. In summary, the morphology of the SCN in tree shrews is described from rostral to caudal. In addition, our data demonstrate for the first time that the SCN in tree shrews receives inputs from numerous brain regions in the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. This comprehensive knowledge of the afferent projections of the SCN in tree shrews provides further insights into the neural organization and physiological processes of circadian rhythms.

Neuropathology of Perry Syndrome: Evidence of Medullary and Hypothalamic Involvement.

Perry syndrome is a rare genetic parkinsonian disorder with TAR DNA binding protein 43 (TDP-43) pathology clinically presenting with parkinsonism, neuropsychiatric features, weight loss, and central hypoventilation. As respiratory complications are often the cause of death, studies likely show the early stage of the neurodegenerative process. Because of the rarity of this condition, few studies exist, and each case provides insight into pathological findings in this neurodegenerative condition. To study the clinical and pathological correlations of an autopsy case of Perry syndrome. The patient was a woman in her 50s with Perry syndrome and a DCTN1 gene mutation. Between October 2016 and July 2019, she underwent postmortem and pathological examination at University Hospital in London, Ontario, Canada. Data were obtained through clinical pathological examination. Microscopy showed significant neuronal loss with pigmentary incontinence and gliosis in the substantia nigra. There was no atrophy elsewhere, including the frontal and cingulate cortex. Intraneuronal cytoplasmic TDP-43 inclusions and neurites were noticed in a moderate number in the substantia nigra and midbrain and were sparsely noticed in the basal ganglia, thalamus, thoracic motor neuron, posterior nucleus of the hypothalamus, and rostral ventral medulla. β-Amyloid, Lewy body, and tau pathologies were absent. Rare axonal swelling was identified at the rostral ventrolateral medulla. This study confirms that Perry syndrome is characterized by TDP-43 pathology with absent Lewy bodies or tau pathology. These findings support the hypothesis of dysfunctional neurons in the medulla and hypothalamus, which may respectively correlate to the clinical symptoms of hypoventilation and weight loss in Perry syndrome.

Optimization of whole-brain rabies virus tracing technology for small cell populations

The lateral hypothalamus (LH) is critically involved in the regulation of homeostatic energy balance. Some neurons in the LH express receptors for leptin (LepRb), a hormone known to increase energy expenditure and decrease energy intake. However, the neuroanatomical inputs to LepRb-expressing LH neurons remain unknown. We used rabies virus tracing technology to map these inputs, but encountered non-specific tracing. To optimize this technology for a minor cell population (LepRb is not ubiquitously expressed in LH), we used LepRb-Cre mice and assessed how different titers of the avian tumor virus receptor A (TVA) helper virus affected rabies tracing efficiency and specificity. We found that rabies expression is dependent on TVA receptor expression, and that leakiness of TVA receptors is dependent on the titer of TVA virus used. We concluded that a titer of 1.0–3.0 × 107 genomic copies per µl of the TVA virus is optimal for rabies tracing. Next, we successfully applied modified rabies virus tracing technology to map inputs to LepRb-expressing LH neurons. We discovered that other neurons in the LH itself, the periventricular hypothalamic nucleus (Pe), the posterior hypothalamic nucleus (PH), the bed nucleus of the stria terminalis (BNST), and the paraventricular hypothalamic nucleus (PVN) are the most prominent input areas to LepRb-expressing LH neurons.

Histamine Activates Chemosensitive Neurons in the Retrotrapezoid Nucleus

Histaminergic neurons of the posterior hypothalamic tuberomammillary nucleus (TMN) are pH-sensitive and contribute to CO2/H+-dependent behaviors including arousal and respiratory activity. Considering histaminergic neurons project to several brainstem respiratory centers including the retrotrapezoid nucleus (RTN), and since chemosensitive RTN neurons are an important source of CO2/H+-dependent respiratory drive, we wondered whether and how histamine contributes to RTN chemoreception at the cellular level and in anesthetized rats. In brain slices obtained from rat pups (7-12 days old), chemosensitive RTN neurons were identified in cell-attached voltage-clamp mode by their characteristic firing response to CO2 (≥ 0.8 Hz increase in activity in response to 10% CO2). We found that most chemosensitive RTN neurons showed a dose dependent increase in activity in response to bath application of histamine dihydrochloride (HD: 1-25 μM). The increased activity of RTN neurons by HD (25 mM) was blunted by bath application of the H1 receptor antagonist DPH (diphenhydramine hydrochloride; 100 µM) (1.1 ± 0.1 Hz to -0.06 ± 0.2 Hz; n = 7) or the H2 receptor antagonist ranitidine (ranitidine hydrochloride; 10 µM) (1.0 ± 0.2 Hz to 0.3 ± 0.3 Hz; n = 5). At the whole animal level, we measured mean arterial pressure (MAP) and diaphragm muscle activity (DIAEMG) in urethane-anaesthetized, vagotomized and artificial ventilated male Wistar rats. Unilateral injection of HD (25 mM - 50 nl) into the RTN increased DIAEMG amplitude (17.41 ± 3.8 vs. saline: 0.55 ± 1.9%) and DIAEMG frequency (4.72 ± 1.7 vs -1.8 ± 1.5) without changes MAP. Bilateral injections of DPH (0.5 mM) into the RTN decreased DIAEMG amplitude (-62.6 ± 14.5. vs. saline: -1.1 ± 1.3%), DIAEMG frequency (-66.4 ± 13.4 vs. saline: -1.5 ± 1.9%) and MAP (-43.67 ± 8,4 vs. saline: -3.2 ± 1.7 mmHg). Despite the strong inhibitory effect of DPH on baseline breathing, the hypercapnic ventilatory response was preserved in urethane-anesthetized rats under these experimental conditions. These results suggest histamine signaling via H1 and H2 receptors modulates activity of RTN neurons and respiratory activity.

Histomorphological Studies on the Different Nuclei of Hypothalamus of Indian Buffalo

Background: Hypothalamus is an integral part of the hypothalamo-hypophyseal ovarian axis. It contains several small nuclei that have been implicated in several specialized functions. It is the master endocrine gland because it regulates the activity of the pituitary. The present investigation was planned to elucidate the histomorphological details of different nuclei in the hypothalamus of Indian buffaloes. Methods: The hypothalami of buffaloes (n =52) were collected from local abattoirs and Teaching Veterinary Clinical Complex, GADVASU, Ludhiana. The tissue samples were collected from three levels i.e. the supraoptic, tuberal and the mamillary region of the hypothalamus and processed for paraffin sectioning and the sections were stained with various stains for histomorphological studies. Result: The well-defined cell groups or nuclei were identified both in the coronal and sagittal sections of the hypothalamus in all the reproductive phases. Eight nuclei were distinctly recognized in buffalo hypothalamus at three levels in the coronal sections of the hypothalamus. At the level of optic chiasma, the nuclei were paraventricular nucleus (PVN), supraoptic nucleus (SON) and preopticnucleus (PON); at the tuberal region, there were arcuate nucleus (AN) and ventromedial nucleus (VMN) and at the mammillary region, the lateral mammillary nucleus (LMN), medial mammillary nucleus (MMN) and posterior hypothalamic nucleus (PHN) were identified. Most of the nuclei consisted of a loose or compact heterogeneous collection of neurons. The neurons of the different nuclei were of variable shape. The cytoplasm contained a varied amount of Nissl material. The neurosecretory substance was peripheral in position. Small to large-sized blood vessels were observed in between the neuronal substance. The size of the neurons varied during different stages of reproduction.

Clinical and Experimental Study on Thermoregulatory System and its Relation with Vasomotor Rhinitis

Introduction
 Much of the perennial cold are of vasomotor origin still a less appreciated phenomenon even among the medical personnel, much of which is dubbed in a cursorily in the clinical analogue of a west paper wrap as ‘allergic rhinitis’. This study was attempted to find out the role of thermoregulatory system with causation of vasomotor rhinitis and assessing role of hypothalamus in causation of vasomotor rhinitis.
 Materials and Methods
 In this study conducted during the period of July 1987 to August 1988, 20 normal adult individuals were taken as control and thermoregulatory study was done on them. The results were compared with cases of vasomotor rhinitis/non-allergic rhinopathy cases. In experimental study thermoregulatory study was done on albino rats before and after stereotaxis of anterior and posterior hypothalamic nuclei and the result were compared before stereotaxis and post stereotaxis.
 Results
 Among human study in clinical subjects, patient suffering from vasomotor rhinitis showed a definite shift towards thermoregulatory imbalance both for generalized body caloric fluctuation and particularly on the nasal mucosa. Post-vidian neurectomy results for thermoregulation test was highly significant. In animal study post-hypothalamic stereotaxis temperature measurement showed minimal depression. Dorsal anterior hypothalamic lesion ablation showed significant derangement in the thermoregulatory tolerance profile of the rats’ belly temperature. Posterior hypothalamic lesion showed that there may be some amount of derangements in the thermoregulatory tolerance, which however is not statistically conclusive. Thermoregulatory control is done at hypothalamus, particularly at anterior hypothalamic nuclei level and posterior hypothalamic nuclei in the brain. Thermoregulatory study proves a close correlation between non allergic rhinitis with imbalance in central thermal regulation by hypothalamus.
 Conclusion
 Thermoregulatory study in control and clinical subjects proves a close correlation between vasomotor rhinitis and sympathetic, parasympathetic system.

Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging.

SummaryMonoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Postnatal Development of the Posterior Hypothalamic Theta Rhythm and Local Cell Discharges in Rat Brain Slices.

Theta rhythms have been recorded from rat brain slices of the posterior hypothalamic area (PHa), including the supramammillary and posterior hypothalamic nuclei. Additionally, in numerous studies theta-related neurons were identified in the PHa according to the classification of Bland and Colom (Progress in Neurobiology, 41, 157-208, 1993). It is currently widely accepted that the PHa contributes to the process of HPC theta frequency programming at least in certain behavioral states. The postnatal development of the HPC and its ability to generate theta has also been a subject of studies. Specifically, it was found that theta oscillations are present in the HPC of 8-10 days old rat pups and turn into a well-synchronized and high-amplitude activity in the following few days. In our current study, we therefore focused on the postnatal development of cholinergically-induced theta rhythm and theta-related neuronal activity in PHa slices obtained from 8 to 24 days old rat pups. Theta activity was observed in the PHa preparations at the age of 8-10 days and then progressively increased its probability of occurrence, amplitude and synchrony up to the age of 22-24 days when it reached a plateau phase. A steady increase in the number of recorded neurons correlated with local theta oscillations was also observed.

The Cerebello-Hypothalamic and Hypothalamo-Cerebellar Pathways via Superior and Middle Cerebellar Peduncle in the Rat.

The connections between the cerebellum and the hypothalamus have been well documented. However, the specific cerebellar peduncle through which the hypothalamo-cerebellar and cerebello-hypothalamic connections pass has not been demonstrated. The present study aims to define the specific cerebellar peduncle through which connects the cerebellum to specific hypothalamic nuclei. Seventeen male albino rats received 20-50-nl pressure injections of either Fluoro-Gold (FG) or biotinylated dextran amine (BDA) tracer into the superior (SCP), middle (MCP), and inferior (ICP) cerebellar peduncle. Following 7-10days of survival period, the animals were processed according to the appropriate protocol for the two tracers used. Labeled cells and axons were documented using light or fluorescence microscopy. The present study showed connections between the hypothalamus and the cerebellum via both the SCP and the MCP but not the ICP. The hypothalamo-cerebellar connections via the SCP were from the lateral, dorsomedial, paraventricular, and posterior hypothalamic nuclei, and cerebello-hypothalamic connections were to the preoptic and lateral hypothalamic nuclei. The hypothalamo-cerebellar connections via the MCP were from the lateral, dorsomedial, ventromedial, and mammillary hypothalamic nuclei; and cerebello-hypothalamic connections were to the posterior, arcuate, and ventromedial hypothalamic nuclei. The hypothlamo-cerebellar connections were denser compared to the cerebello-hypothlamic connections via both the SCP and the MCP. The connection between the cerebellum and the hypothalamus was more prominent via the SCP than MCP. Both the hypothlamo-cerebellar and cerebello-hypothalamic connections were bilateral, with ipsilateral preponderance. Reciprocal connections were with the lateral hypothalamic nucleus via the SCP and the ventromedial nucleus via the MCP were observed. Cerebellum takes part in the higher order brain functions via its extensive connections. The knowledge of hypothalamo-cerebellar and cerebello-hypothalamic connections conveyed within the SCP and MCP can be important for the lesions involving the MCP and SCP. These connections can also change the conceptual architecture of the cerebellar circuitry and deepen current understanding.

The modulation of hippocampal theta rhythm by the vestibular system.

The vestibular system is a sensory system that has evolved over millions of years to detect acceleration of the head, both rotational and translational, in three dimensions. One of its most important functions is to stabilize gaze during unexpected head movement; however, it is also important in the control of posture and autonomic reflexes. Theta rhythm is a 3- to 12-Hz oscillating EEG signal that is intimately linked to self-motion and is also known to be important in learning and memory. Many studies over the last two decades have shown that selective activation of the vestibular system, using either natural rotational or translational stimulation, or electrical stimulation of the peripheral vestibular system, can induce and modulate theta activity. Furthermore, inactivation of the vestibular system has been shown to significantly reduce theta in freely moving animals, which may be linked to its impairment of place cell function as well as spatial learning and memory. The pathways through which vestibular information modulate theta rhythm remain debatable. However, vestibular responses have been found in the pedunculopontine tegmental nucleus (PPTg) and activation of the vestibular system causes an increase in acetylcholine release into the hippocampus, probably from the medial septum. Therefore, a pathway from the vestibular nucleus complex and/or cerebellum to the PPTg, supramammillary nucleus, posterior hypothalamic nucleus, and septum to the hippocampus is likely. The modulation of theta by the vestibular system may have implications for vestibular effects on cognitive function and the contribution of vestibular impairment to the risk of dementia.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability.

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep.SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal.