The organization of the thalamic midline efferents to the amygdaloid complex, hippocampal formation, and nucleus accumbens was investigated in the rat by means of multiple retrograde fluorescent tracing. The present findings indicate that these connections derive from separate cell populations of the thalamic midline, with a low degree of divergent collateralization upon more than one of the targets examined. The neural populations projecting to the amygdala, hippocampus, or accumbens are highly intermingled throughout the thalamic midline, but display some topographical prevalence. Midline thalamo-hippocampal cells are concentrated in the nucleus reuniens; thalamo-accumbens neurons prevail in the ventral portion of the paraventricular nucleus, and in the central medial nucleus. Thalamo-amygdaloid cells display a topographical prevalence in the rostral third of the thalamic midline and are concentrated in the dorsal part of the paraventricular nucleus and in the medial part of the nucleus reuniens. Both dorsally in the paraventricular nucleus and ventrally in the nucleus reuniens, thalamo-amygdaloid cells are located closer to the ependymal lining than the neurons projecting to the hippocampus or nucleus accumbens. Further, thalamo-amygdaloid cells, especially in the paraventricular nucleus, extend their dendritic processes in the vicinity of the ependymal lining, where they arborize profusely. These features indicate a close topographical relationship of neurons projecting to the amygdala with ependymal cells. The fairly discrete origin of midline outputs to the amygdala, hippocampus, and accumbens indicates that the flow of information is conveyed through separate channels from the thalamic midline to limbic and limbic-related targets. Together with the literature on the limbic afferents to the thalamus, these findings emphasize the relationships between the thalamus and the limbic system subserved by parallel input-output routes. However, because of the overlap of the projection cell populations, the thalamic midline may represent a locus of interaction among neurons connected with different parts of the limbic system. The functional implications of these findings are discussed in relation to the "nonspecific" thalamic system, as well as to the circuits involved in memory formation.

Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB 1 )-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB 1 -expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB 1 -expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB 1 -expressing axon terminals. Patchclamp recordings also showed increased CB 1 -sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB 1 -mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB 1 -mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.food intake | orexin-A/hypocretin 1 | high-fat diet | retrograde signaling M odulation of the activity of hypothalamic neurons is involved in the regulation of energy balance exerted by the adipose tissue-derived hormone leptin. In the arcuate nucleus (ARC), these neurons express either pro-opiomelanocortin (POMC) and cocaine and amphetamine-responsive transcript, or neuropeptide Y (NPY) and agouti-related peptide (AgRP). Orexigenic neurons containing the peptide hypocretin-1/orexin-A (hereafter referred to as OX) reside in the lateral hypothalamus (LH) and send projections throughout the brain (1). They have been implicated in a variety of functions, including wakefulness and energy homeostasis (2), behavioral responses to food reward (3, 4) and addictive drugs (5), and neuroendocrine and autonomic outflow (6-8).Short-term food deprivation results in decreased activity of POMC neurons and increased activity of NPY/AgRP neurons, thus facilitating food consumption (9). Such deprivation also causes enhancement of excitatory inputs to OX neurons. Reduction in leptin levels is responsible for these alterations, as they are reversed by administration of the hormo...

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