Functional asymmetry in the descending cardiovascular pathways from dorsomedial hypothalamic nucleus

Neurons in the dorsomedial hypothalamus (DMH) play a key role in mediating tachycardia elicited by emotional stress. DMH activation by microinjections of the GABA_A antagonist evokes tachycardia and physiological changes typically seen in experimental stress. DMH inhibition abolishes the tachycardia evoked by stress. Based on anatomic evidences for lateralization in the pathways from DMH, we investigated a possible inter-hemispheric difference in DMH-evoked cardiovascular responses. In anesthetized rats we compared changes in heart rate (HR), renal sympathetic activity (RSNA), mesenteric blood flow (MBF) and tail vascular conductance produced by activation of right (R) and left (L) sides of the DMH. We also evaluated the tachycardia produced by air jet stress after inhibition of R or L DMH. There were always greater increases in RSNA when bicuculline was injected ipsilaterally to the side where these parameters were recorded (average ΔRSNA: L=+50% and R=+26%; P<0.05). Compared to pre-injection values, right DMH activation caused pronounced decrease (0.87±0.1% vs. 0.4±0.11%/mm Hg; P<0.05), whereas bicuculline methiodide (BMI) into left DMH produced no significant changes (0.95±0.09% vs. 1.04±0.25%/mm Hg) in tail vascular conductance. R or L DMH disinhibition produced decreases in MBF, but no differences in the range of these changes were observed. Activation of the right DMH caused greater tachycardia compared to the left DMH activation (average ΔHR: R=+92 bpm; L=+48 bpm; P<0.05). Tachycardia evoked by air jet stress was smallest after right DMH inhibition (average ΔHR: R=+57 bpm and L=+134 bpm; P<0.05). These results indicate that the descending cardiovascular pathways from DMH are predominantly lateralized and the right DMH might exert a prominent control on heart rate changes during emotional stress.     

Connections of the dorsomedial hypothalamic nucleus from the forebrain structures in the rat

The dorsomedial hypothalamic nucleus (DMH) has been implicated as an area controlling autonomic activity. The aim of this study was to demonstrate connections of the anterior and posterior DMH to the forebrain structures, using a horseradish peroxidase (HRP) retrograde axonal transport technique in rats. The results of HRP labelling show that the anterior and posterior DMH indicate a number of differences in their connections. The posterior DMH has intense connections with the cortex (cingulate, frontal, parietal and insular), amygdala (lateral and basolateral) and hippocampus (CA1 and CA2), whereas the anterior DMH has faint connections with the cortex (cingulate, frontal and parietal) and prominent connections with the septal and bed nucleus of stria terminalis. These differences in connections of the DMH may provide sites for the specific autonomic function integrated by the DMH.     

Effect of insulin in rats with lesions of the dorsomedial hypothalamic nucleus.

Four hours after insulin injection Dorsomedial Hypothalamic Nuclei (DMN) lesioned rats consumed an amount of food that was comparable to that eaten by injected sham-operated animals. However, the DMN lesioned rats are not as initially responsive to the food intake stimulating properties of insulin as are the controls. A second study showed ad lib fed and fasted lesioned animals displayed a lower plasma glucose concentration after insulin challenge than did respectively treated controls. This suggests the initial insulin-induced feeding of the lesioned rats was blunted when compared to the controls even in the face of lower plasma glucose levels. Although a previous investigation revealed that DMN lesions destroy glucoreceptor tissue, the present data shows that DMN lesioned rats will increase their food intake in the face of insulin challenge, albeit their initial feeding response to insulin challenge is somewhat blunted. Finally, the present study confirms a previous report in that DMN lesioned rats can competently meter their 24 hour calorie intake.     

Growth hormone secretion and ultradian rhythms in growth-retarded rats with dorsomedial hypothalamic lesions

Rats with lesions of the dorsomedial nucleus of the hypothalamus (DMN-L) are hypophagic and have reduced linear growth and body weight, but normal body composition. Male Sprague-Dawley rats (170-190 g) housed individually under a 12:12 L:D schedule with lights out at 1430 hr received jugular cannulas, and on return to precannulation body weight (4.2 +/- 0.6 days), they received bilateral electrolytic DMN-L or sham-operations (SHAM). Rats with DMN-L (n = 8) were hypophagic postsurgery and weight less (p less than 0.05) than SHAM at six days postlesion surgery. The difference in body weight between the two groups continued to expand over the next four weeks. Six days postsurgery, the rats were bled (RBC's returned in 10% BSA-saline) every 15 minutes between 0600-1215 hr and growth hormone (GH) subsequently assayed. The total GH secretion, as computed from the area under each rat's ultradian pattern, was similar in both groups (DMN-L versus SHAM, 2952.2 +/- 346.5 versus 2950.4 +/- 337.5). Using the PULSAR computer program, the baseline secretion (12.2 +/- 4.0 versus 11.8 +/- 2.7 ng/ml), total number of peaks (2.4 +/- 0.4 versus 2.4 +/- 0.2), and interpeak interval (2.8 +/- 0.5 versus 2.7 +/- 0.4, hr) were not significantly different between the DMN-L and SHAM rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous circadian rhythms in rats recovered from lateral hypothalamic lesions

Compared with intact controls, rats which have recovered spontaneous ingestion after lateral hypothalamic lesions show exaggerated nocturnal rhythms. Food intake was low and water intake negligible in the light part of a LD 12:12 cycle. The endogenous rhythms persisted in constant dark, and were clearly free running in constant light with periods of 25–26 hr. Animals with relatively asymmetric damage showed strong LL suppression of intake on the first day; animals with symmetric damage showed no LL suppression and the strongest free running rhythms; rats with the largest lesions showed a permanent LL suppression of fluid intake from Day 3 onward. The LL rhythms were rapidly reentrained with a restored LD cycle, with phase shifts of over 90°/24 hr. Recovered laterals which were previously blinded by orbital enucleation showed free running rhythms with periods close to 24 hr. The division of the 24 hr period into active (α) and quiescent (?) phases is much more sharply defined after the lesion. This is especially marked for drinking; feeding and activity rhythms are very similar. It is suggested that the recovered lateral is dependent upon endogenous oscillator(s) subserving motivated behaviors, and implications for the recovery of function and residual impairments are discussed.     

Lesions of the suprachiasmatic nucleus disrupt circadian locomotor rhythms in the mouse

Entrained and free-running rhythms of wheel-running activity were recorded in male BALB/cByJ mice with electrolytic lesions of the suprachiasmatic nucleus (SCN), site of a circadian pacemaker in mammals. Complete ablation of the nucleus abolished the circadian locomotor rhythm; in some cases, wheel-running was synchronized by a light-dark cycle, but the phase relationship of this activity to the cycle was often aberrant. Unilateral lesions or those missing the SCN did not eliminate rhythmicity.     

Entrainment of circadian rhythms: Retinofugal pathways and unilateral suprachiasmatic nucleus lesions

The role of retinohypothalamic input to the suprachiasmatic nuclei (SCN) as well as SCN afferents from the ventrolateral geniculate nuclei (LGN_v) in the entrainment of circadian drinking rhythms was investigated in the rat. Bilateral lesions of the LGN_v and the primary optic tracts had no affect on the entrainment of drinking rhythms to a light-dark cycle, the response to a 12 hr phase shift of the light-dark cycle, or on the period of the free-running circadian rhythm in constant light or constant darkness. Unilateral blinding in rats with or without LGN_v lesions retarded the rate of phase shifting by 2 days and decreased the period of the free-running rhythm in constant light. For rats with unilateral SCN lesions, or such lesions combined with either ipsi- or contra-lateral blinding, the rate of re-entrainment was intermediate between intact and unilaterally blinded rats indicating that unilateral SCN lesions partially reversed the effects of unilateral blinding. Unilateral SCN lesions had no effect on the period of the free-running rhythm in constant light or darkness. These results are consistent with the interpretation that the asymmetrical innervation of the two SCN by the RHT in unilaterally blinded rats delays re-entrainment by changing the phase response curve of the circadian system. This change may be mediated by neural connections between the two SCN.     

Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei

Although pinealectomy has little effect on the generation of circadian rhythmicity by mammals, daily injections of the pineal hormone melatonin entrain free-running rats [30]. The present study was designed to determine if known components of mammalian circadian organization were necessary for melatonin entrainment. Rats received either lesions to the suprachiasmatic nuclei (SCN), sham-lesions or neurotoxic lesions to brain catecholamines or serotonin. They were then allowed to free-run in constant dim red light (DD) before each received daily injections of either 1 mg/kg melatonin or ethanol:saline vehicle for 90 days. They were allowed to free-run for 30 days afterwards. Rats which received sham-lesions or neurotoxic lesions entrained to melatonin injections but not to vehicle. Rats which received complete SCN lesions were unaffected by melatonin or vehicle. These data suggest that the behavioral effects of melatonin, like those on reproduction in seasonally breeding mammals, depend upon an intact circadian system and the SCN.     

Constant light housing attenuates circadian rhythms of mPer2 mRNA and mPER2 protein expression in the suprachiasmatic nucleus of mice

Constant light (LL) or constant dark (DD) environmental lighting conditions cause a free-running period and activity reduction in the rodent behavioral circadian rhythm. In order to understand the molecular process underlying behavioral rhythms in LL or DD housing conditions, we examined the circadian profile of mPer2 mRNA and mPER2 in the suprachiasmatic nucleus (SCN), a main oscillator, of free-running mice. The circadian expression rhythm of mPer2 in the SCN was dampened under 7-day LL conditions, whereas that of mPER2 protein was moderately attenuated and its expression peak delayed. The circadian expression of mPer2 and its product was slightly attenuated and advanced by 7-day DD conditions. With arrhythmic behavioral activity caused by long-term LL housing, mPER2 protein lost its rhythmicity in the SCN. On the other hand, LL or DD housing did not affect the mPer2 gene and its product in the cerebral cortex. The present results suggest that mPER2 circadian expression in the SCN corresponds well with behavioral circadian oscillation under LL or DD conditions. Thus, the behavioral circadian rhythm seems to correlate with molecular clock works in the SCN.     

Development of the circadian rhythm of neuronal activity in suprachiasmatic nucleus of rat hypothalamic slices

Development of the circadian rhythm of neuronal activity in the suprachiasmatic nucleus (SCN) was studied in rat hypothalamic slices. The firing rate of SCN neurons of 7- and 11-day-old rat pups was low during all of the day, whereas that of 14- and 21-day-old pups was high during daytime and low during nighttime. The present results suggest that the circadian rhythm of SCN neuronal activity is established between 11 and 14 days of age, corresponding closely to the time of onset of the other various hormonal and behavioral circadian rhythms.     

Central oxytocin potentiates excitatory responses of oxytocin neurones to stimulation of the dorsomedial hypothalamic nucleus in the suckled rat.

Experiments were undertaken to investigate the effects of intracerebroventricular (i.c.v.) oxytocin (OT) on the response of supraoptic OT neurones to stimulation of the dorsomedial nucleus (DMH), in the suckled lactating rat. Under control conditions, the majority of OT neurones displayed either weak excitation to DMH stimulation, or no response. Following i.c.v. OT injection, all neurones showed a pronounced long-latency (70-115 ms) excitatory response, and the number of spikes evoked per stimulus pulse was significantly increased. This increased excitatory response was accompanied by facilitation of the milk-ejection reflex. Some OT neurones also displayed a short latency (8-13 ms) excitation to DMH stimulation, but this was unaffected by i.c.v. OT. In conclusion, the facilitation of bursting in OT neurones by i.c.v. OT is associated with potentiation of long-latency excitatory responses evoked by DMH stimulation.