A sexually dimorphic hypothalamic circuit controls maternal care and oxytocin secretion.

It is commonly assumed, but has rarely been demonstrated, that sex differences in behaviour arise from sexual dimorphism in the underlying neural circuits. Parental care is a complex stereotypic behaviour towards offspring that is shared by numerous species. Mice display profound sex differences in offspring-directed behaviours. At their first encounter, virgin females behave maternally towards alien pups while males will usually ignore the pups or attack them. Here we show that tyrosine hydroxylase (TH)-expressing neurons in the anteroventral periventricular nucleus (AVPV) of the mouse hypothalamus are more numerous in mothers than in virgin females and males, and govern parental behaviours in a sex-specific manner. In females, ablating the AVPV TH(+) neurons impairs maternal behaviour whereas optogenetic stimulation or increased TH expression in these cells enhance maternal care. In males, however, this same neuronal cluster has no effect on parental care but rather suppresses inter-male aggression. Furthermore, optogenetic activation or increased TH expression in the AVPV TH(+) neurons of female mice increases circulating oxytocin, whereas their ablation reduces oxytocin levels. Finally, we show that AVPV TH(+) neurons relay a monosynaptic input to oxytocin-expressing neurons in the paraventricular nucleus. Our findings uncover a previously unknown role for this neuronal population in the control of maternal care and oxytocin secretion, and provide evidence for a causal relationship between sexual dimorphism in the adult brain and sex differences in parental behaviour.

Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response.

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.

[Changes in metabolic activity of neurons in the anterior hypothalamus nuclei during hyperthermia, fever, and hypothermia]. / Izmeneniia metabolicheskoi aktivnosti neironov iader perednego gipotalamusa krys pri gipertermii, likhoradke i gipotermii.

Differently directed changes in metabolic activity of anterior hypothalamic nuclei's neurons in rats during hyperthermia, fever, and hypothermia were revealed with histochemical methods. During hyperthermia, the activity of energy metabolism enzymes increased as well as RNA content in the neurons of supraoptic, paraventricular and median preoptic anterior hypothalamic nuclei. This is shown by an increase in the metabolic activity of neurons of these nuclei. Metabolic activity in neurons of median preoptic nuclei decreased and was not changed considerably in neurons of supraoptic and paraventricular nuclei during endotoxin-induced fever. The development of hypothermia was characterised by a decrease in metabolic activity of neurons of supraoptic, paraventricular and medium preoptic nuclei. It is supposed that differently directed metabolic activity changes in neurons of anterior hypothalamic nuclei during hyperthermia are connected with the mechanisms of body temperature regulation (median preoptic nuclei) and neurosecretory processes (supraoptic and paraventricular nuclei).

Neonatal handling and the expression of immunoreactivity to tyrosine hydroxylase in the hypothalamus of adult male rats

Neonatal handling has long-lasting effects on behavior and stress reactivity. The purpose of the present study was to investigate the effect of neonatal handling on the number of dopaminergic neurons in the hypothalamic nuclei of adult male rats as part of a series of studies that could explain the long-lasting effects of neonatal stimulation. Two groups of Wistar rats were studied: nonhandled (pups were left undisturbed, control) and handled (pups were handled for 1 min once a day during the first 10 days of life). At 75-80 days, the males were anesthetized and the brains were processed for immunohistochemistry. An anti-tyrosine hydroxylase antibody and the avidin-biotin-peroxidase method were used. Tyrosine hydroxylase-immunoreactive (TH-IR) neurons were counted bilaterally in the arcuate, paraventricular and periventricular nuclei of the hypothalamus in 30-æm sections at 120-æm intervals. Neonatal handling did not change the number of TH-IR neurons in the arcuate (1021 + or - 206, N = 6; 1020 + or - 150, N = 6; nonhandled and handled, respectively), paraventricular (584 + or - 85, N = 8; 682 + or - 62, N = 9) or periventricular (743 + or - 118, N = 7; 990 + or - 158, N = 7) nuclei of the hypothalamus. The absence of an effect on the number of dopaminergic cells in the hypothalamus indicates that the reduction in the amount of neurons induced by neonatal handling, as shown by other studies, is not a general phenomenon in the brain

Neonatal handling and the expression of immunoreactivity to tyrosine hydroxylase in the hypothalamus of adult male rats.

Neonatal handling has long-lasting effects on behavior and stress reactivity. The purpose of the present study was to investigate the effect of neonatal handling on the number of dopaminergic neurons in the hypothalamic nuclei of adult male rats as part of a series of studies that could explain the long-lasting effects of neonatal stimulation. Two groups of Wistar rats were studied: nonhandled (pups were left undisturbed, control) and handled (pups were handled for 1 min once a day during the first 10 days of life). At 75-80 days, the males were anesthetized and the brains were processed for immunohistochemistry. An anti-tyrosine hydroxylase antibody and the avidin-biotin-peroxidase method were used. Tyrosine hydroxylase-immunoreactive (TH-IR) neurons were counted bilaterally in the arcuate, paraventricular and periventricular nuclei of the hypothalamus in 30-microm sections at 120-microm intervals. Neonatal handling did not change the number of TH-IR neurons in the arcuate (1021 +/- 206, N = 6; 1020 +/- 150, N = 6; nonhandled and handled, respectively), paraventricular (584 +/- 85, N = 8; 682 +/- 62, N = 9) or periventricular (743 +/- 118, N = 7; 990 +/- 158, N = 7) nuclei of the hypothalamus. The absence of an effect on the number of dopaminergic cells in the hypothalamus indicates that the reduction in the amount of neurons induced by neonatal handling, as shown by other studies, is not a general phenomenon in the brain.

[The enzymatic activity of the neurosecretory nuclei of the anterior hypothalamus in exposure of the body to organophosphorus compounds]. / Aktivnost' fermentov neirosekretornykh iader perednego gipotalamusa pri vozdeistvii na organizm fosfororganicheskikh soedinenii.

Under study were activities of glycolysis enzymes: LDH, Krebs' cycle--SDH, those of electron transport system--NAD and NADP-diaphorase, and of the hydrolytic enzymes, acid and alkaline phosphatases in the hypothalamus, as were morphofunctional shifts in these enzymes' activities in poisoning with organophosphorus compounds. The experiments were carried out in 72 white male outbred rats weighing 180-200 g, that were administered PHOS antio (an organo-phosphorus compound) in a daily dose of 0.1 LD50 for 30 days. Early dates of poisoning were associated with an essential rise of the redox enzymes and a lowering of the hydrolytic enzymes levels, this being paralleled by morphologic signs of activation of the neurosecretory cells. Later high levels of neurosecretory material in the neurosecretory nuclei and reduced counts of neurosecretory cells were coupled with almost all the enzymes' activities lowering. This permits a conclusion that changed activities of the enzymic systems may be one of the pathogenetic mechanisms and possible causes of neurosecretory cell dysfunction in pesticide poisonings.

Neurons containing messenger RNA encoding glutamate decarboxylase in rat hypothalamus demonstrated by in situ hybridization, with special emphasis on cell groups in medial preoptic area, anterior hypothalamic area and dorsomedial hypothalamic nucleus.

Previous deafferentation studies have suggested that most hypothalamic GABAergic innervation originates from neurons within the hypothalamus. We have investigated the distribution of GABAergic cell groups in the rat hypothalamus by means of the in situ hybridization technique, using a cDNA probe for messenger RNA encoding glutamate decarboxylase. Several major GABAergic cell groups were demonstrated, including cells of the tuberomammillary nucleus, arcuate nucleus, suprachiasmatic nucleus, medial preoptic area, anterior hypothalamic area, the dorsomedial hypothalamic nucleus, perifornical area, and lateral hypothalamic area. The most prominent glutamate decarboxylase mRNA-containing cell groups were located in the medial preoptic area, anterior hypothalamic area and dorsomedial hypothalamic nucleus, and were composed of small- to medium-sized neurons. Compared to previously well-characterized GABAergic cell groups in the tuberomammillary nucleus, reticular thalamic nucleus, and non-pyramidal cells of cerebral cortex, the cells of these GABAergic groups demonstrated only weak cDNA labelling, indicating that they contain lower levels of glutamate decarboxylase mRNA. Several types of control experiments supported the specificity of this cDNA labelling, and the GABAergic nature of these cell populations was further supported by detection of glutamate decarboxylase and GABA immunoreactivity. Abundance of GABAergic cells in many hypothalamic nuclei indicates that GABA represents quantitatively the most important transmitter of hypothalamic neurons, and may be involved in neuroendocrine and autonomic regulatory functions.

In vivo biosynthesis of two subunit forms of dopamine beta-hydroxylase in rat brain.

In vivo biosynthesis of the 2 subunit forms of dopamine beta-hydroxylase (DBH) was examined in the rat brain. 35S-methionine was injected into the noradrenergic neurons of the locus coeruleus (LC) using a stereotactic device. Several hours later, newly synthesized 35S-Met-labeled DBH was immunoprecipitated and quantitated. Both Mr = 77,000 (77K) and 73,000 (73K) subunit forms were present in near-equal proportions after 4 hr of labeling, and these were indistinguishable from those isolated from rat PC12 pheochromocytoma cells by electrophoretic mobility. Both forms sedimented with the vesicular subcellular fraction of LC homogenates, and a portion of the 73K form could be released by hypotonic lysis of these vesicles. The 77K form predominated in the first 30 min labeling period, while the 73K form appeared more slowly over the next several hours. By 16 hr, the 73K form comprised about 2/3 of the total 35S-Met-labeled DBH present. Inhibition of protein synthesis with puromycin 30 min after 35S-Met injection into the LC did not prevent the subsequent appearance of the 73K form, suggesting that this subunit form was the product of posttranslational modification of the 77K subunit form in a fashion similar to that seen in PC12 cells. Also, newly synthesized 35S-Met-labeled DBH that underwent axonal transport from the LC to the anterior hypothalamus was predominantly the 73K subunit form. A single injection of the catecholamine-depleting drug reserpine (10 mg/kg, i.p.) produced a 17-fold increase in the relative synthesis of DBH 2 d later without affecting the proportion of its 2 subunit forms.