Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse.

The tachykinins substance P (SP) and neurokinin A (Tac1) have emerged as novel regulators of kisspeptin/GnRH release. Recently, we documented that SP modulates reproductive function in the female mouse. Here, we extended this characterization to the male mouse.

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.

Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined.

Electrophysiology of kisspeptin neurons.

Kisspeptin is an important regulator of reproduction. Electrophysiological studies show that kisspeptin neurons of the arcuate nucleus that co-localize neurokinin B and dynorphin (aka KNDy neurons) fire action potentials in a tonic, irregular, or burst firing manner. Gonadectomy dramatically alters the membrane properties of KNDY neurons from male mice and induces somatic hypertrophy.

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile.

Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism.

The novel hypothalamic peptides avian gonadotropin inhibitory hormone (GnIH) and its mammalian analogue RFRP-3, are emerging as key negative regulators of reproductive functions across species. GnIH/RFRP-3 reduces gonadotropin release and may play an inhibitory role in ovulation and seasonal reproduction, actions opposite to that of the puberty-promoting kisspeptins. GnIH directly inhibits gonadotropin release from the anterior pituitary in birds.

Excitatory effects of the puberty-initiating peptide kisspeptin and group I metabotropic glutamate receptor agonists differentiate two distinct subpopulations of gonadotropin-releasing hormone neurons.

Activation of the G-protein-coupled receptor GPR54 by kisspeptins during normal puberty promotes the central release of gonadotropin-releasing hormone (GnRH) that, in turn, leads to reproductive maturation. In humans and mice, a loss of function mutations of GPR54 prevents the onset of puberty and leads to hypogonadotropic hypogonadism and infertility. Using electrophysiological, morphological, molecular, and retrograde-labeling techniques in brain slices prepared from vGluT2-GFP and GnRH-GFP mice, we demonstrate the existence of two physiologically distinct subpopulations of GnRH neurons.

Neurokinins robustly activate the majority of septohippocampal cholinergic neurons.

In the brain, tachykinins acting via the three cloned neurokinin (NK) receptors are implicated in stress-related affective disorders. Hemokinin-1 is a novel tachykinin that reportedly prefers NK1 to NK2 or NK3 receptors. Although NK1 and NK3 receptors are abundantly expressed in the brain, NK2-receptor-mediated electrophysiological effects have rarely been described as NK2 receptors are expressed only in a few brain regions such as the nucleus of the medial septum/diagonal band.

Muscarine activates the sodium-calcium exchanger via M receptors in basal forebrain neurons.

Neurons of the medial septum/diagonal band of Broca (MSDB) project to the hippocampus. Muscarinic cholinergic mechanisms within the MSDB are potent modulators of hippocampal functions; intraseptal scopolamine disrupts and intraseptal carbachol facilitates hippocampus-dependent learning and memory tasks, and the associated hippocampal theta rhythm. In earlier work, we demonstrated that, within the MSDB, the septohippocampal GABAergic but not cholinergic neurons are the primary target of muscarinic manipulations and that muscarinic activation of septohippocampal GABAergic neurons is mediated directly via M(3) receptors.

Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release.

Recent studies indicate that the histaminergic system, which is critical for wakefulness, also influences learning and memory by interacting with cholinergic systems in the brain. Histamine-containing neurones of the tuberomammillary nucleus densely innervate the cholinergic and GABAergic nucleus of the medial septum/diagonal band of Broca (MSDB) which projects to the hippocampus and sustains hippocampal theta rhythm and associated learning and memory functions. Here we demonstrate that histamine, acting via H(1) and/or H(2) receptor subtypes, utilizes direct and indirect mechanisms to excite septohippocampal GABA-type neurones in a reversible, reproducible and concentration-dependent manner.

Intrinsic vesicular glutamate transporter 2-immunoreactive input to septohippocampal parvalbumin-containing neurons: novel glutamatergic local circuit cells.

Glutamatergic influence on the medial septum diagonal band of Broca complex (MSDB) is a crucial and powerful driver of hippocampal theta rhythm and associated memory processes, in the rat. The recent discovery of vesicular glutamate transporters (VGLUT) provided a specific marker for glutamatergic neuronal elements. Therefore, this study aimed to address two specific questions: (1) do glutamatergic axons innervate MSDB gamma-aminobutyric acid (GABA)ergic, parvalbumin (PV)-containing septohippocampal neurons that are known to have a great influence on the electric activity of the hippocampus; and (2) is the origin of these glutamatergic axons extrinsic and/or intrinsic to the septum.

Hippocampal theta rhythm is reduced by suppression of the H-current in septohippocampal GABAergic neurons.

Hippocampal learning and memory tasks are tightly coupled to the hippocampal theta rhythm, which is critically dependent on the medial septum/diagonal band of Broca (MSDB) although the underlying mechanisms remain unclear. The MSDB sends both cholinergic and GABAergic projections to the hippocampus. Here we show that: (i) septo-hippocampal GABAergic but not cholinergic neurons have a pacemaking current, the H-current, and that its selective blockade by ZD7288 reduces their spontaneous firing in rat brain slices; and (ii), local infusions of ZD7288 into the MSDB reduce exploration and sensory evoked hippocampal theta bursts in behaving rats.

Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons.

Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics.

Group I metabotropic glutamate receptor activation produces a direct excitation of identified septohippocampal cholinergic neurons.

Septohippocampal cholinergic neurons innervate the hippocampus and provide it with almost its entire acetylcholine. Axon collaterals of these neurons also release acetylcholine within the septum and thereby maintain the firing activity of septohippocampal GABAergic neurons. A loss of septohippocampal cholinergic neurons occurs in various neurodegenerative disorders associated with cognitive dysfunctions.

Acetylcholinesterase inhibitors activate septohippocampal GABAergic neurons via muscarinic but not nicotinic receptors.

Acetylcholinesterase (AChE) inhibitors, which increase synaptic levels of available acetylcholine (ACh) by preventing its degradation, are the most extensively prescribed drugs for the treatment of Alzheimer's disease. In animals, AChE inhibitors improve learning and memory, reverse scopolamine-induced amnesia, and produce hippocampal theta rhythm. The medial septum/diagonal band of Broca (MSDB), which maintains hippocampal theta rhythm and associated mnemonic functions via the septohippocampal pathway, is considered a critical locus for mediating the effects of AChE inhibitors.

Nicotine recruits a local glutamatergic circuit to excite septohippocampal GABAergic neurons.

Tonic impulse flow in the septohippocampal GABAergic pathway is essential for normal cognitive functioning and is sustained, in part, by acetylcholine (ACh) that is released locally via axon collaterals of septohippocampal cholinergic neurons. Septohippocampal cholinergic neurons degenerate in Alzheimer's disease and other neurodegenerative disorders. While the importance of the muscarinic effects of ACh on septohippocampal GABAergic neurons is well recognized, the nicotinic effects of ACh remain unstudied despite the reported benefits of nicotine on cognitive functioning.

Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition.

Hypocretins (Hcrts), or orexins, are a recently described set of hypothalamic peptides that have been implicated in feeding, neuroendocrine regulation, sleep-wakefulness, and disorders of sleep, such as narcolepsy. Hcrt-containing neurons, which are located exclusively in the lateral hypothalamic area, provide a dense innervation to the medial septum/diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions that occur during exploratory behavior and rapid eye movement sleep.

The formalin test: a tonic pain model in the primate.

The formalin test has been used in monkeys for assessing pain. After formalin injection in the palmar surface of the hand just proximal to the base of the fingers, the monkey's responses are rated for 1 h according to objective behavioral criteria. The present 'tonic' pain model has a fair degree of objectivity, validity, reproducibility and quantifiability.