Csaba Leranth

Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals

Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor–deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.

Glutamic Acid Decarboxylase-Containing Axons Synapse on LHRH Neurons in the Rat Medial Preoptic Area

A double-label electron microscopic immunostaining procedure was employed to examine the interconnections of glutamic acid decarboxylase(GAD)- and LHRH-immunoreactive neurons in the medial preoptic area of the rat. The results provide ultrastructural evidence that GABA-ergic neurons establish symmetric (Gray II) synapses on LHRH neurons.

Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations

Neuropeptide Y, produced in the arcuate nucleus of the hypothalamus, plays a key role in the central regulation of anterior pituitary and appetitive functions. The pleiotropic nature of neuropeptide Y in these mechanisms indicates the existence of heterogeneity in the hypothalamic neuronal population producing neuropeptide Y. In this study, we report the coexistence of neuropeptide Y and the amino acid transmitter, gamma-aminobutyric acid (GABA), in neuronal perikarya of the arcuate nucleus. Fluorescent double immunolabeling for neuropeptide Y and glutamic acid decarboxylase was carried out on vibratome sections collected through the hypothalamic arcuate nuclei of animals that were pretreated with colchicine. It was found that about one third of the neuropeptide Y-producing arcuate nucleus perikarya co-expressed glutamic acid decarboxylase. This population of neuropeptide Y-containing GABAergic neurons were distributed longitudinally within the arcuate nucleus located predominantly in its dorsomedial aspects. These results show that there are at least two distinct populations of neuropeptide Y-producing neurons in the arcuate nucleus: a subset of neuropeptide Y and GABA-co-producing neurons located in the dorsomedial arcuate nucleus and a subset of non-GABAergic neuropeptide Y cells located in the ventral arcuate nucleus. This heterogeneity in the neuropeptide Y-producing perikarya of the hypothalamus may help explain adverse neuroendocrine and behavioral effects of arcuate nucleus neuropeptide Y.

Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory.

There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinsons disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinsons disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.

Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus.

The pathomechanism of major depressive disorder and the neurobiological basis of antidepressant therapy are still largely unknown. It has been proposed that disturbed hippocampal activity could underlie some of the cognitive and vegetative symptoms of depression, at least in part because of loss of pyramidal cell synaptic contacts, a process that is likely to be reversed by antidepressant treatment. Here we provide evidence that daily administration of the antidepressant fluoxetine to ovariectomized female rats for 5 days induces a robust increase in pyramidal cell dendritic spine synapse density in the hippocampal CA1 field, with similar changes appearing in CA3 after 2 weeks of treatment. This rapid synaptic remodelling might represent an early step in the fluoxetine‐induced cascade of responses that spread across the entire hippocampal circuitry, leading to the restoration of normal function in the hippocampus. Hippocampal synaptic remodelling might provide a potential mechanism to explain certain aspects of antidepressant therapy and mood disorders, especially those associated with changes in reproductive state in women, that cannot be reconciled adequately with current theories for depression.

Nucleus reuniens of the midline thalamus: Link between the medial prefrontal cortex and the hippocampus

The medial prefrontal cortex and the hippocampus serve well recognized roles in memory processing. The hippocampus projects densely to, and exerts strong excitatory actions on, the medial prefrontal cortex. Interestingly, the medial prefrontal cortex, in rats and other species, has no direct return projections to the hippocampus, and few projections to parahippocampal structures including the entorhinal cortex. It is well established that the nucleus reuniens of the midline thalamus is the major source of thalamic afferents to the hippocampus. Since the medial prefrontal cortex also distributes to nucleus reuniens, we examined medial prefrontal connections with populations of nucleus reuniens neurons projecting to hippocampus. We used a combined anterograde and retrograde tracing procedure at the light and electron microscopic levels. Specifically, we made Phaseolus vulgaris-leuccoagglutinin (PHA-L) injections into the medial prefrontal cortex and Fluorogold injections into the hippocampus (CA1/subiculum) and examined termination patterns of anterogradely PHA-L labeled fibers on retrogradely FG labeled cells of nucleus reuniens. At the light microscopic level, we showed that fibers from the medial prefrontal cortex form multiple putative synaptic contacts with dendrites of hippocampally projecting neurons throughout the extent of nucleus reuniens. At ultrastructural level, we showed that medial prefrontal cortical fibers form asymmetric contacts predominantly with dendritic shafts of hippocampally projecting reuniens cells. These findings indicate that nucleus reuniens represents a critical link between the medial prefrontal cortex and the hippocampus. We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism.

Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates

Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agencys reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.

Androgen modulation of hippocampal synaptic plasticity

This review briefly summarizes recent developments in our understanding of the role of androgens in maintaining normal hippocampal structure. Studies in rats and vervet monkeys have demonstrated that removal of the testes reduces the density of synaptic contacts on dendritic spines of cornu ammonis 1 (CA1) pyramidal neurons. This effect is rapidly reversed by treatment with either testosterone or the non-aromatizable androgen dihydrotestosterone, suggesting that maintenance of normal synaptic density is androgen-dependent, via a mechanism that does not require intermediate estrogen biosynthesis. Similar effects of these androgens are observed in ovariectomized female rats, except that in the female the actions of testosterone include a substantial contribution from estrogen formation. The ability to stimulate hippocampal spine synapse density is not directly related to systemic androgenic potency: thus, weak androgens such as dehydroepiandrosterone exert effects that are comparable to those of dihydrotestosterone; while partial agonist responses are observed after injection of the synthetic antiandrogen, flutamide. These data provide a morphological counterpart to observations that androgens enhance cognitive function and mood state, suggesting that these effects may result at least in part from hippocampal neurotrophic responses. The unusual specificity of these responses raises the possibility that effects of androgens on the brain may be mediated via different mechanisms than the masculinizing actions of these steroids in non-neural androgen target organs.

The Environmental Estrogen Bisphenol A Inhibits Estradiol-Induced Hippocampal Synaptogenesis

Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, as well as the BPA-containing plastics used in dental prostheses and sealants, considerable potential exists for human exposure to this compound. In this article we show that treatment of ovariectomized rats with BPA dose-dependently inhibits the estrogen-induced formation of dendritic spine synapses on pyramidal neurons in the CA1 area of the hippocampus. Significant inhibitory effects of BPA were observed at a dose of only 40 μg/kg, below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Because synaptic remodeling has been postulated to contribute to the rapid effects of estrogen on hippocampus-dependent memory, these data suggest that environmental BPA exposure may interfere with the development and expression of normal sex differences in cognitive function, via inhibition of estrogen-dependent hippocampal synapse formation. It may also exacerbate the impairment of hippocampal function observed during normal aging, as endogenous estrogen production declines.

Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression

BACKGROUND Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. METHODS We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. RESULTS Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects. CONCLUSIONS These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.