TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex.

Synaptic plasticity is one of the putative mechanisms involved in the maturation of the prefrontal cortex (PFC) during postnatal development. Early life stress (ELS) affects the shaping of cortical circuitries through impairment of synaptic plasticity supporting the onset of mood disorders. Growing evidence suggests that dysfunctional postnatal maturation of the prelimbic division (PL) of the PFC might be related to the emergence of depression. The potassium channel TREK-1 has attracted particular interest among many factors that modulate plasticity, concerning synaptic modifications that could underlie mood disorders. Studies have found that ablation of TREK-1 increases the resilience to depression, while rats exposed to ELS exhibit higher TREK-1 levels in the PL. TREK-1 is regulated by multiple intracellular transduction pathways including the ones activated by metabotropic receptors. In the hippocampal neurons, TREK-1 interacts with the serotonergic system, one of the main factors involved in the action of antidepressants. To investigate possible mechanisms related to the antidepressant role of TREK-1, we used brain slice electrophysiology to evaluate the effects of TREK-1 pharmacological blockade on synaptic plasticity at PL circuitry. We extended this investigation to animals subjected to ELS. Our findings suggest that in non-stressed animals, TREK-1 activity is required for the reduction of synaptic responses mediated by the 5HT1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT1A receptor stimulation. On the other hand, in ELS animals, TREK-1 blockade reduces synaptic transmission and facilitates LTD expression. These results indicate that TREK-1 inhibition stimulates synaptic plasticity in the PL and this effect is more pronounced in animals subjected to ELS during postnatal development.

Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice.

Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1-expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhrlit/lit mice). Interestingly, although Ghrhrlit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhrlit/lit mice. Despite presenting dwarfism, the majority of Ghrhrlit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1-expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice.

Postnatal Overnutrition Induces Changes in Synaptic Transmission to Leptin Receptor-Expressing Neurons in the Arcuate Nucleus of Female Mice.

The adipocyte-derived hormone leptin is a potent neurotrophic factor that contributes to the neural plasticity and development of feeding circuitry, particularly in the arcuate nucleus of the hypothalamus (ARH). Postnatal overnutrition affects leptin secretion and sensitivity, but whether postnatal overnutrition produces changes in the development of the synaptic transmission to ARH neurons is currently unknown. We evaluated the excitatory and inhibitory currents to ARH leptin receptor (LepR)-expressing neurons in prepubertal, pubertal and adult female mice. The effects of postnatal overnutrition in the expression of genes that code ion channels subunits in the ARH were also evaluated. We observed that the transition from prepubertal to pubertal stage is characterized by a rise in both excitatory and inhibitory transmission to ARH LepR-expressing neurons in control mice. Postnatal overnutrition induces a further increase in the excitatory synaptic transmission in pubertal and adult animals, whereas the amplitude of inhibitory currents to ARH LepR-expressing cells was reduced. Postnatal overnutrition also contributes to the modulation of gene expression of N-methyl-D-aspartate, GABAB and ATP-sensitive potassium channel subunits in ARH. In summary, the synaptic transmission to ARH cells is profoundly influenced by postnatal overnutrition. Thus, increased adiposity during early postnatal period induces long-lasting effects on ARH cellular excitability.

Evaluation of food intake and Fos expression in serotonergic neurons of raphe nuclei after intracerebroventricular injection of adrenaline in free-feeding rats.

Previous studies indicate that the modification of adrenergic neurotransmission in median raphe nucleus (MRN) enhances or removes an inhibitory influence on food intake, possibly serotonergic, due to a presence of serotonin-producing neurons in that nucleus. Therefore, the aim of this study is evaluated whether the activity of neurons in the MRN and dorsal raphe nucleus (DRN) are affected by intracerebroventricular injection of adrenaline (AD) in free-feeding rats. Male Wistar rats with guide cannulae chronically implanted in the lateral ventricle were injected with AD followed by evaluation of ingestive behavioral parameters. Behavior was monitored and the amount of food ingested was assessed. The highest dose (20 nmol) of AD was the most effective dose in increasing food intake. Subsequently, AD 20 nmol was injected to study neuronal activity indicated by the presence of Fos protein and its co-localization with serotonergic neurons in the MRN and DRN of naive rats with or without access to food during the recording of behavior. The administration of AD 20 nmol increased Fos expression and double labeling with serotonergic neurons in the DRN in rats with access to food, but not in animals without access. No statistically significant changes in Fos expression were observed in the MRN in any of the experimental conditions tested. These results suggest that DRN serotonergic and non-serotonergic neurons are activated by post-prandial signals. In contrast, the absence of Fos expression in the MRN suggests that this nucleus does not participate in the circuit involved in the control of post-prandial satiety.

SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet.

Pregnancy induces transitory metabolic changes including increases in food intake and body fat deposition, as well as leptin and insulin resistance. Recent findings have suggested that increased hypothalamic expression of suppressor of cytokine signaling-3 (SOCS3) is a key mechanism responsible for triggering those metabolic adaptations. Because obesity is a risk factor for gestational metabolic imbalances, we aimed to study the role of SOCS3 during pregnancy in obese mice. Female mice carrying a deletion of SOCS3 in leptin receptor-expressing cells (SOCS3 KO mice) were exposed to a chronic high-fat diet (HFD), and we then studied their energy balance and glucose homeostasis during pregnancy. SOCS3 deletion did not prevent diet-induced obesity or changes in body weight and adiposity observed during pregnancy. However, the typical increase in food intake during mid- and late-pregnancy was blunted in SOCS3 KO females. We also observed a slight improvement in glucose homeostasis and increased leptin sensitivity in the arcuate nucleus of the hypothalamus in pregnant SOCS3 KO mice on HFD. Despite this, SOCS3 KO mice had an increased number of uterine reabsorptions and fewer fetuses compared to the controls. Compared to control animals, a reduction in proopiomelanocortin and an increase in oxytocin mRNA levels were observed in the hypothalamus of pregnant SOCS3 KO mice. In contrast to previous studies using lean animals, conditional SOCS3 ablation did not prevent major gestational metabolic changes in diet-induced obese mice. Our findings contribute to the understanding of the role of SOCS3 in mediating pregnancy-induced metabolic adaptations.