Restriction of food intake by PPP1R17-expressing neurons in the DMH.

Leptin-deficient ob/ob mice eat voraciously, and their food intake is markedly reduced by leptin treatment. In order to identify potentially novel sites of leptin action, we used PhosphoTRAP to molecularly profile leptin-responsive neurons in the hypothalamus and brainstem. In addition to identifying several known leptin responsive populations, we found that neurons in the dorsomedial hypothalamus (DMH) of ob/ob mice expressing protein phosphatase 1 regulatory subunit 17 (PPP1R17) constitutively express cFos and that this is suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that activating PPP1R17 neurons would increase food intake. However, chemogenetic activation of PPP1R17 neurons decreased food intake and body weight of ob/ob mice while inhibition of PPP1R17 neurons increased them. Similarly, in a scheduled feeding protocol that elicits increased consumption, mice also ate more when PPP1R17 neurons were inhibited and ate less when they were activated. Finally, we found that pair-feeding of ob mice reduced cFos expression to a similar extent as leptin and that reducing the amount of food available during scheduled feeding in DMHPpp1r17 neurons also decreased cFos in DMHPpp1r17 neurons. Finally, these neurons do not express the leptin receptor, suggesting that the effect of leptin on these neurons is indirect and secondary to reduced food intake. In aggregate, these results show that PPP1R17 neurons in the DMH are activated by increased food intake and in turn restrict intake to limit overconsumption, suggesting that they function to constrain binges of eating.

Blockade of the dorsomedial hypothalamus and the perifornical area inhibits respiratory responses to arousing and stressful stimuli.

The dorsomedial hypothalamus (DMH) and the perifornical area (DMH/PeF) is one of the key regions of central autonomic processing. Previous studies have established that this region contains neurons that may be involved in respiratory processing; however, this has never been tested in conscious animals. The aim of our study was to investigate the involvement of the DMH/PeF area in mediating respiratory responses to stressors of various intensities and duration. Adult male Wistar rats (n = 8) received microinjections of GABAA agonist muscimol or saline into the DMH/PeF bilaterally and were subjected to a respiratory recording using whole body plethysmography. Presentation of acoustic stimuli (500-ms white noise) evoked transient responses in respiratory rate, proportional to the stimulus intensity, ranging from +44 ± 27 to +329 ± 31 cycles/min (cpm). Blockade of the DMH/PeF almost completely abolished respiratory rate and tidal volume responses to the 40- to 70-dB stimuli and also significantly attenuated responses to the 80- to 90-dB stimuli. Also, it significantly attenuated respiratory rate during the acclimatization period (novel environment stress). The light stimulus (30-s 2,000 lux) as well as 15-min restraint stress significantly elevated respiratory rate from 95 ± 4.0 to 236 ± 29 cpm and from 117 ± 5.2 to 189 ± 13 cpm, respectively; this response was abolished after the DMH/PeF blockade. We conclude that integrity of the DMH/PeF area is essential for generation of respiratory responses to both stressful and alerting stimuli.

Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis.

Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 µg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 µL, 0.25 µL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40-min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 min after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5 to 2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame.

A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses.

Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.

Hypothalamic endocannabinoid signalling modulates aversive responses related to panic attacks.

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB1 and CB2 antagonists (AM251 and AM630, respectively), and mimicked by CB1 and CB2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB1 and CB2 receptors in this brain region.

Influence of hypothalamic stimulation on the development of status epilepticus in rats.

The main objectives of the present study were to explore whether emotional behavior, elicited by stimulation of the dorso-medial hypothalamus, can influence seizure development during self-sustained status epilepticus (SSSE). The study was conducted on animal models. The results suggest that increased inhibition in the hippocampal neurons during dorsomedial hypothalamic stimulation may trigger the mechanisms preventing the epileptiform activity and that hippocampal theta rhythm is a physiological state, which opposes its involvement into seizures. It was concluded that activation of the dorsomedial hypothalamus, as well as emotional behavior (anxiety/fear) retard development of the seizures experimentally induced SSSE by limbic stimulation.

Role of the orexin 2 receptor in palatable-food consumption-associated cardiovascular reactivity in spontaneously hypertensive rats.

Hypertensive subjects often exhibit exaggerated cardiovascular reactivity. An overactive orexin system underlies the pathophysiology of hypertension. We examined orexin's roles in eating-associated cardiovascular reactivity in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Results showed eating regular chow or palatable food (sucrose agar) was accompanied by elevated arterial pressure and heart rate. In both SHRs and WKY rats, the cardiovascular responses associated with sucrose-agar consumption were greater than that with regular-chow consumption. Additionally, SHRs exhibited greater cardiovascular responses than WKY rats did to regular-chow and palatable food consumption. Central orexin 2 receptor (OX2R) blockade attenuated sucrose-agar consumption-associated cardiovascular response only in SHRs. In both SHRs and WKY rats, OX2R blockade did not affect regular-chow consumption-associated cardiovascular responses. Greater numbers of c-Fos-positive cells in the rostral ventrolateral medulla (RVLM) and of c-Fos-positive orexin neurons in the dorsomedial hypothalamus (DMH) were detected in sucrose agar-treated SHRs, compared to regular chow-treated SHRs and to sucrose agar-treated WKY rats. Central OX2R blockade reduced the number of c-Fos-positive cells in the RVLM only in sucrose agar-treated SHRs. We concluded that in SHRs, orexin neurons in the DMH might be overactive during eating palatable food and may further elicit exaggerated cardiovascular responses via an OX2R-RVLM pathway.

Brain Activity during Methamphetamine Anticipation in a Non-Invasive Self-Administration Paradigm in Mice.

The ability to sense time and anticipate events is critical for survival. Learned responses that allow anticipation of the availability of food or water have been intensively studied. While anticipatory behaviors also occur prior to availability of regularly available rewards, there has been relatively little work on anticipation of drugs of abuse, specifically methamphetamine (MA). In the present study, we used a protocol that avoided possible CNS effects of stresses of handling or surgery by testing anticipation of MA availability in animals living in their home cages, with daily voluntary access to the drug at a fixed time of day. Anticipation was operationalized as the amount of wheel running prior to MA availability. Mice were divided into four groups given access to either nebulized MA or water, in early or late day. Animals with access to MA, but not water controls, showed anticipatory activity, with more anticipation in early compared to late day and significant interaction effects. Next, we explored the neural basis of the MA anticipation, using c-FOS expression, in animals euthanized at the usual time of nebulization access. In the dorsomedial hypothalamus (DMH) and orbitofrontal cortex (OFC), the pattern of c-FOS expression paralleled that of anticipatory behavior, with significant main and interaction effects of treatment and time of day. The results for the lateral septum (LS) were significant for main effects and marginally significant for interaction effects. These studies suggest that anticipation of MA is associated with activation of brain regions important in circadian timing, emotional regulation, and decision making.

Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors.

Rats with chronic inhibition of GABA synthesis and consequently enhanced glutamatergic excitation in the dorsomedial hypothalamus (DMH) develop panic-like responses, defined as tachycardia, tachypnea, hypertension, and increased anxiety as measured by a social interaction (SI) test, after intravenous sodium lactate infusions, a phenomenon similar to patients with panic disorder. Therefore, the present studies tested the role of the postsynaptic NMDA and AMPA type glutamatergic receptors in the lactate-induced panic-like responses in these rats. Rats were fit with femoral arterial and venous catheters and Alzet pumps [filled with the GABA synthesis inhibitor L-allylglycine (L-AG; 3.5 nmol/0.5 microl per hour) or its inactive isomer D-AG] into the DMH. After 4-5 d of recovery only those rats with L-AG pumps exhibited panic-like responses to lactate infusions. Using double immunocytochemistry, we found that rats exhibiting panic-like responses (e.g., L-AG plus lactate) had increased c-Fos immunoreactivity in DMH neurons expressing the NMDA receptor 1 (NR1) subunit, but not those expressing the glutamate receptor 2 and 3 subunits of the AMPA receptors. To confirm this pharmacologically, we tested another group of rats implanted with l-AG pumps with intravenous lactate infusions preceded by injections of either NMDA [aminophosphonopentanoic acid (AP-5) or (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801)] or non-NMDA [CNQX or 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodazepin-5-yl)-benzenamine dihydrochloride (GYKI52466)] antagonists into the DMH. Injections of NMDA, but not non-NMDA, antagonists into the DMH resulted in dose-dependent blockade of the tachycardia, tachypnea, hypertension, and SI responses after lactate infusions. These results suggest that NMDA, and not non-NMDA, type glutamate receptors regulate lactate-induced panic-like responses in rats with GABA dysfunction in the DMH.

Stress-induced alterations in catecholamine enzymes gene expression in the hypothalamic dorsomedial nucleus are modulated by caudal brain and not hypothalamic paraventricular nucleus neurons.

The hypothalamic dorsomedial nucleus (DMN) represents an important coordinate center for regulation of autonomic and neuroendocrine systems, especially during stress response. The present study was focused on the gene expression of catecholamine-synthesizing enzymes and the protein levels of tyrosine hydroxylase in DMN, both in control and stressed rats. Moreover, pathways modulating the gene expression of tyrosine hydroxylase in DMN during immobilization (IMO) stress were also investigated. Gene expressions of all catecholamine-synthesizing enzymes were detected in DMN samples. While the levels of tyrosine hydroxylase and phenylethanolamine N-methyltransferase mRNA were increased in IMO rats, aromatic L-amino acid decarboxylase and dopamine-beta-hydroxylase mRNA remained unchanged. Tyrosine hydroxylase protein levels were significantly elevated in the DMN only after repeated IMO stress. Postero-lateral deafferentations of the DMN, or transections of the ascending catecholaminergic pathways originating in the lower brainstem abolished the IMO-induced increase of tyrosine hydroxylase gene expression in the DMN. Nevertheless, postero-lateral deafferentations of the hypothalamic paraventricular nucleus (PVN), which separate the DMN from the PVN, had no effect on IMO-induced elevation of tyrosine hydroxylase mRNA in the DMN. The present data indicate that certain DMN neurons synthesize mRNA of catecholamine enzymes. The stress-induced increase of tyrosine hydroxylase and phenylethanolamine N-methyltransferase mRNA in DMN neurons indicates the involvement of these catecholaminergic neurons in stress response. The gene expression of tyrosine hydroxylase in DMN is modulated by lower brainstem and/or spinal cord, but not by PVN afferents.

Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations.

Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsα expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia. Although maternal Gnas deletion impaired activation of brown adipose tissue (BAT) in mice, their responses to cold environment remained intact. Similar findings were observed in mice with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate Gsα. Our results show that Gsα imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from Gsα mutations and that DMH MC4R/Gsα signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold.

[A case of left dorsomedial thalamic infarction with unilateral schizophrenia-like auditory hallucinations].

We report a case of a right-handed, 73-year-old woman with auditory hallucinations lateralized to the right ear. A brain MRI revealed a small infarction in the left dorsomedial nucleus (DM) of the thalamus. The patient did not have either psychiatric or neurological prior history, and had otherwise been treated for ischemic heart disease, hypertension, and hyperlipidemia for 10 years. Two months prior to admission, she had become forgetful, and had lost her wallet several times. She concurrently began to experience auditory hallucinations in which she heard the voices of her acquaintances, or "the gods". She frequently monologized and wandered about outside following the contents of the hallucinations. Therefore, she was admitted to our institution. On admission, no apparent abnormalities were revealed by physical examinations or blood analyses. She was alert and had no aphasic symptoms. Except for memory disturbances, no neurological symptoms, including no hearing loss, were found. A brain MRI showed a small localized infarction in the left DM, but EEG findings were normal. The patient had prominent anterograde memory deficits: she hardly remembered what she had done the very same day, or the names of the doctor and hospital. She also demonstrated a retrograde amnesia of the past decade or two: she showed difficulty recalling either personal history or social events that occurred during this era. Wechsler Adult Intelligence Scale-Revised (WAIS-R) revealed a total IQ of 75 (verbal IQ 77; performance IQ 77). The verbal hallucinations continued with frequent occurrence even after admission. They included voices telling her about misfortunes, such as death or sickness, of her relatives. These turned into threats and commands, such as "I'm gonna kill ya. I attack you from behind. You, do not eat!" In addition, she occasionally experienced "third person auditory hallucination", in which several men were discussing the plan to kill her. As is characteristic of this type of case, the hallucinations always appeared in only her right ear. They did not occur in the other modalities (e.g. as a visual one). She was convinced that the hallucinations were real and looked frightened while they were happening. Whereas the anterograde amnesia continued for 6 months after admission, the retrograde amnesia gradually improved within 2 or 3 months after admission, although a partial amnesia on the past decade eventually turned out to persistent. On the other hand, the hallucinations did not ameliorate satisfactorily with risperidone (3-6 mg/day), but on augmentation with olanzapine (5-20 mg/day), they lessened gradually and almost disappeared within 6 months. She also slowly developed symptoms similar to those of frontal lobe syndrome, i.e., aspontaneity and apathy. In conclusion, our case indicates the importance of DM on memory function. It is noteworthy that schizophrenia-like hallucinations developed in the case. Localized neuronal deficits evoked by infarction in the left DM probably caused the schizophrenia-like hallucinations; the lateralization phenomenon further indicates the involvement of specific neuronal mechanisms in the mediation of the hallucinations. According to the knowledge of the functional anatomy of the DM and the lateralization phenomenon of auditory hallucinations, it is possible that the neuronal loop, comprised of the prefrontal cortex and thalamus, designated as "basal ganglia-thalamocortical circuits", in addition to the left temporal cortex, plays an important role in the development of the hallucinations in this case. This possibility might also shed light on the neurological basis of schizophrenia.

Median nerve stimulation reduces ventricular arrhythmias induced by dorsomedial hypothalamic stimulation.

BACKGROUND: This study tested the hypothesis that median nerve stimulation (MNS) prevents ventricular arrhythmias (VAs) induced by dorsomedial hypothalamus stimulation (DMHS) and investigated the electrophysiological mechanisms underlying the anti-arrhythmic effects of MNS by recording left stellate ganglion activity (LSGA). METHODS: Eighteen rabbits were anesthetized, the median nerve was anchored by stimulating electrodes, and a bipolar electrode was implanted into the LSG to record nerve activity. The DMH was stimulated to induce arrhythmia. All animals underwent six repetitions of DMHS (30 s). The 18 rabbits were divided into the following 3 groups: a control group, which underwent only DMHS (n = 6); an MNS group, which underwent MNS during both the third and fourth DMHS repetitions (n = 6); and an LSGA-recording group, for which LSGA was recorded at baseline, immediately following DMHS and again immediately following MNS and DMHS (n = 6). RESULTS: Repeated DMHS-induced multiple VAs, in the rabbits. Compared with the DMHS-only group, the concurrent administration of MNS during DMHS significantly reduced the incidence of VAs (7 ± 3 and 9 ± 2 beats for the third and fourth DMHS + MNS repetitions vs. 29 ± 8 and 27 ± 9 beats for the first two DMHS repetitions, p < 0.05). The total duration of the abnormal discharges of the LSG (ADLSG) following MNS and DMHS was significantly reduced compared with that of the DMHS-only group (40 ± 18 vs. 14 ± 6 s, p < 0.05). CONCLUSION: MNS reduced VAs induced by DMHS, which is thought to be mediated through suppressing of ADLSG. NEW AND NOTEWORTHY: Median nerve electrical stimulation prevented ventricular arrhythmias induced by DMHS through the mechanism of suppressing abnormal discharges of left stellate ganglion.

Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety.

Trial 2 in the elevated plus-maze provides an animal model of specific phobia (fear of heights). On this trial, rats no longer respond to benzodiazepines. The present experiment examined the role of the dorsomedial hypothalamus in mediating insensitivity to chlordiazepoxide on trial 2. Rats received a 5 min exposure to the maze, undrugged. Forty-eight hours later, rats injected with control infusions into the dorsomedial hypothalamus showed the usual lack of response to chlordiazepoxide (5 mg/kg, i.p.). However, those receiving lidocaine injections (40 micrograms/microliter in a volume of 0.2 microliter) in the dorsomedial hypothalamus (producing functional inactivation), immediately before trial 2, responded with an anxiolytic response to chlordiazepoxide, characterised by an increased percentage of time on the open arms and by an increased number of entries into, and time spent on, the distal portions of the open arms. Since the lidocaine injections were without anxiolytic effects, our results suggest that this region of the hypothalamus regulates the functional state of benzodiazepine receptors in other brain regions.

The effect of dorsomedial hypothalamic nucleus lesions on kidney function and structure after 1 and 12 months.

According to the Dillman theory (17), aging results from a deterioration of metabolism that begins with an elevation of hypothalamic receptor thresholds for feedback signals from the periphery. Three hypothalamic areas are known to contain such receptors: the ventromedial and dorsomedial hypothalamic nuclei (DMN) and the lateral hypothalamic area. We have hypothesized that selective destruction of those hypothalamic areas might be followed by physiological changes associated with aging. Electrolytic bilateral DMN lesions were produced in male and female weanling rats. These rats were maintained for up to 13 months of age. Sham-operated rats served as controls. Food intake and body weight were monitored postoperatively and prior to sacrifice. Before sacrifice, tail blood and a 24-h urine samples were obtained. In accordance with previous findings, rats with DMN lesions showed dramatic reductions of ponderal growth and food intake but had normal body composition. Total protein and albumin excretion rates were significantly lower in rats with lesions. The fractional contribution of albumin to total urinary protein was also decreased in rats with lesions. Histological examination of the kidneys showed significantly less pathology in the kidneys of rats with DMN lesions; the severity of renal pathology was correlated directly with proteinuria. These changes were seen as early as 1 month after production of the lesion. The attenuation of age-related changes in kidney functions and structure in rats with lesions could be due to reduced food intake (dietary restriction is known to produce similar results), and/or a direct effect of the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effect of brain-stem vasomotor centers on the neurogenic control of cerebrovascular tonus--Part 3. The effects of destruction and stimulation of the brain-stem on intracranial pressure in acute subarachnoid hemorrhage].

The purpose of the present study is to clarify the effects of destruction and stimulation of the brain-stem on intracranial pressure (ICP) in experimentally induced subarachnoid hemorrhage (SAH). Using 23 cats, blood pressure (BP), ICP and local cerebral blood volume (CBV) were continuously measured. Acute SAH was produced by injection of autogenous blood (3 to 7 ml) into the cisterna magna. The animals were divided into two groups. Group A: those in which hypothalamic dorsomedial nucleus (DM) and reticular formation of the midbrain (MBRF) were coagulated bilaterally one hour after SAH and Group B: in addition to the procedure of Group A, reticular formation of the medulla oblongata (MORF) was electrically stimulated bilaterally. In 19 out of 23 cats of both groups, transient small increases in ICP and CBV were observed during coagulation and/or stimulation of DM, MBRF and MORF respectively in the animals whose ICP remained approximately 20 mmHg or below and progressive increase in ICP was never evoked. In 3 animals of Group A whose ICPs remained high at more than 20 mmHg, sequential destruction of DM and MBRF induced stepwise increase in ICP to 40 to 80 mmHg and consequently resulted in acute brain swelling. In 1 animal of Group B whose ICP fluctuated around 20 to 40 mmHg, biphasic increase in ICP to 100 mmHg was repeatedly evoked by stimulation of MORF. It is concluded that in the condition of increased ICP produced by SAH, lesions in the DM and MBRF and stimulating condition of MBRF may result in acute brain swelling.

[Morpho-functional status of large-cell hypothalamic nuclei following chronic exposure to wide-range electromagnetic impulses]. / Morfofunktsional'noe sostoianie krupnokletochnykh iader gipotalamusa pri khronicheskom vozdeistvii shirokopolosnykh élektromagnitnykh impul'sov.

In a experiment with white nubilous male rats the morphofuntional state of secretory neurons (SN) of the large-cell hypothalamic nuclei (LCHN) was evaluated with the morphological, morphometric and statistical methods following electromagnetic exposure (500, 100 and 50 impulses once a week) inducing in the animal body the averaged current densities of 1.5 kA/m2. It was stated that 100 EMI a week called forth opposite LCHN reactions, that is suppression of synthesis and elimination of SN neuro-secret in supraoptic nuclei and their activation in the paraventricular nuclei. LCHN reaction to the other frequencies of EM impulses was uniform and included rearrangement of both neurosecretory centers for a lower functional activity. Decrease in the number of effectively functioning SN due to the EM exposure may point to a dead-aptive effect of this factor.

The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.

While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK2 receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.

Inhibitory function of the dorsomedial hypothalamic nucleus on the hypothalamic-pituitary-adrenal axis response to an emotional stressor but not immune challenge.

Accumulating evidence implicates the dorsomedial hypothalamic nucleus (DMH) in the regulation of autonomic and neuroendocrine stress responses. However, although projections from the DMH to the paraventricular hypothalamic nucleus (PVN), which is the critical site of the neuroendocrine stress axis, have been described, the impact of DMH neurones in the modulation of hypothalamic-pituitary-adrenal (HPA) axis activation during stress is not fully understood. The present study aimed to investigate the role of the DMH in HPA axis responses to different types of stimuli. Male Sprague-Dawley rats fitted with a chronic jugular venous catheter were exposed to either an emotional stressor (elevated platform-exposure) or immune challenge (systemic interleukin-1ß administration). Bilateral electrolytic lesions of the DMH disinhibited HPA axis responses to the emotional stressor, as indicated by higher plasma adrenocorticotrophic hormone levels during and after elevated platform exposure in lesioned animals compared to sham-lesioned controls. Moreover, DMH-lesioned animals showed increased neuronal activation in the PVN, as indicated by a higher c-Fos expression after elevated-platform exposure compared to controls. By contrast, DMH-lesions had no effects on HPA axis responses to immune challenge. Taken together, our data suggest an inhibitory role of DMH neurones on stress-induced HPA axis activation that is dependent upon the nature of the stimulus being important in response to an emotional stressor but not to immune challenge.