The hypothalamus is the gray matter of the ventral portion of the diencephalon. The hypothalamus is the higher center of the autonomic nervous system and is involved in the regulation of various homeostatic mechanisms. It also modulates respiration by facilitating the respiratory network. Among subregions of the hypothalamus, the paraventricular nucleus, lateral hypothalamic area, perifornical area, dorsomedial and posterior hypothalamus play particularly important roles in respiratory control. Neurons in these regions have extensive and complex interconnectivity with the cerebral cortex, pons, medulla, spinal cord, and other brain areas. These hypothalamic regions are involved in the maintenance of basal ventilation, respiratory responses to hypoxic and hypercapnic conditions, respiratory augmentation during dynamic exercise, and respiratory modulation in awake and sleep states. Disorders affecting the hypothalamus such as narcolepsy, ROHHAD syndrome, and Prader-Willi syndrome could lead to respiratory abnormalities. However, the role of the hypothalamus in respiratory control, especially its interplay with other local respiratory networks has not yet been fully elucidated. Further clarification of these issues would contribute to a better understanding of the hypothalamus-mediated respiratory control and the pathophysiology of respiratory disorders underlain by hypothalamic dysfunction, as well as to the development of new targeted therapies.

Kisspeptin (KISS1), originally catalogued as metastin because of its capacity as a metastasis suppressor in human melanoma and breast cancer, is now recognized as the major puberty gatekeeper and gonadotropin-releasing hormone (GnRH) neuroendocrine system modulator. It is a member of the family of RFamide-related peptidesthat also includes the neuropeptide FF group, the gonadotropin-inhibitory hormone, the prolactin-releasing peptide, and the 26RFa peptides. The KISS1 precursor peptide is processed into a family of peptides known as kisspeptins. Its expression has been described in the hypothalamus as well as in the whole reproductive axis and several extra reproductive tissues of mammals as well as fish and amphibians, but not in birds. KISS1 plays an essential role as a regulator of the reproductive axis by inducing the synthesis and release of GnRH, acting through specific receptors. The study of the kisspeptin system and its relation with reproduction in wild and non-classical laboratory species is extremely useful to understand and become aware of the role of KISS1 in the wide variety of possible different reproductive strategies. In this chapter, KISS1 involvement in non-classical laboratory rodents, fishes, and birds is discussed.

The hypothalamus, in addition to controlling the main body's vital functions, is also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular pathways, including Ca2+ signaling and neuronal excitability in the brain. Intrinsic electrophysiological properties of individual neurons and synaptic transmission between cells is disrupted in the central nervous system of old animals. However, changes in neuronal excitability and excitation/inhibition balance with aging are specific to the type of neurons, brain region, and species. Glia-neuron interactions play a significant role in the brain and undergo remodeling accompanied by advanced loss of function with aging. In the current review, I have summarized the current understanding of the changes in the brain and especially in the hypothalamus with aging.

The hypothalamus is one of the most complex region in the central nervous system regarding neuroanatomy, neurochemical content, neuropeptide/classical neurotransmitter interactions, physiological actions, and pathophysiology. Hypothalamic neuropeptides have been involved in a large plethora of mechanisms related with obesity, anxiety, feeding, energy metabolism, defensive behavior, mood, and reproduction. The therapeutic potential of these findings is enormous but the physiological complexity occurring in the hypothalamus is huge due in part to the interactions between numerous neuropeptides as well as between neuropeptides and other neuroactive substances. Here, we review the development and neuroanatomy of the hypothalamus as well as the involvement of 31 neuropeptides in hypothalamic functions and pathologies. Alterations in the secretion, release, and/or concentrations of neuropeptides and/or their hypothalamic receptors can trigger different pathologies. Several therapeutic strategies that could be carried out by adjusting neuropeptide levels in the hypothalamus are suggested. The combination of imaging techniques with a detailed neurochemical knowledge of the hypothalamus would be an excellent diagnostic tool, allowing personalized treatment. Several approaches for future research that may contribute to improve or resolve these pathologies are also mentioned.

Sleep is a physiological process that preserves the integrity of the neuro-immune-endocrine network to maintain homeostasis. Sleep regulates the production and secretion of hormones, neurotransmitters, cytokines and other inflammatory mediators, both at the central nervous system (CNS) and at the periphery. Sleep promotes the removal of potentially toxic metabolites out of the brain through specialized systems such as the glymphatic system, as well as the expression of specific transporters in the blood-brain barrier. The blood-brain barrier maintains CNS homeostasis by selectively transporting metabolic substrates and nutrients into the brain, by regulating the efflux of metabolic waste products, and maintaining bidirectional communication between the periphery and the CNS. All those processes are disrupted during sleep loss. Brain endothelial cells express the blood-brain barrier phenotype, which arises after cell-to-cell interactions with mural cells, like pericytes, and after the release of soluble factors by astroglial endfeet. Astroglia, pericytes and brain endothelial cells respond differently to sleep loss; evidence has shown that sleep loss induces a chronic low-grade inflammatory state at the CNS, which is associated with blood-brain barrier dysfunction. In animal models, blood-brain barrier dysfunction is characterized by increased blood-brain barrier permeability, decreased tight junction protein expression and pericyte detachment from the capillary wall. Blood-brain barrier dysfunction may promote defects in brain clearance of potentially neurotoxic metabolites and byproducts of neural physiology, which may eventually contribute to neurodegenerative diseases. This chapter aims to describe the cellular and molecular mechanisms by which sleep loss modifies the function of the blood-brain barrier.

Cholesterol, an essential and versatile lipid, is the precursor substrate for the biosynthesis of steroid hormones, and a key structural and functional component of organelle membranes in eukaryotic cells. Consequently, the framework of steroidogenesis across main steroidogenic cell types is built around cholesterol, including its cellular uptake, mobilization from intracellular storage, and finally, its transport to the mitochondria where steroidogenesis begins. This setup, which is controlled by different trophic hormones in their respective target tissues, allows steroidogenic cells to meet their steroidogenic need of cholesterol effectively without impinging on the basic need for organelle membranes and their functions. However, our understanding of the basal steroidogenesis (i.e., independent of trophic hormone stimulation), which is a cell-intrinsic trait, remains poor. Particularly, the role that cholesterol itself plays in the regulation of steroidogenic factors and events in steroid hormone-producing cells remains largely unexplored. This is likely because of challenges in selectively targeting the steroidogenic intracellular cholesterol pool in studies. New evidence suggests that cholesterol plays a role in steroidogenesis. These new findings have created new opportunities to advance our understanding in this field. In this book chapter, we will provide a cholesterol-centric view on steroidogenesis and emphasize the importance of the interplay between cholesterol and the mitochondria in steroidogenic cells. Moreover, we will discuss a novel mitochondrial player, prohibitin-1, in this context. The overall goal is to provide a stimulating perspective on cholesterol as an important regulator of steroidogenesis (i.e., more than just a substrate for steroid hormones) and present the mitochondria as a potential cell-intrinsic factor in regulating steroidogenic cholesterol homeostasis.

Accumulation of glycation products in patients with hyperglycaemic conditions can lead to their reaction with the proteins in the human system such as serum albumin, haemoglobin, insulin, plasma lipoproteins, lens proteins and collagen among others which have important biological functions. Therefore, it is important to understand if glycation of these proteins affects their normal action not only qualitatively, but also importantly quantitatively. Glycation of human serum albumin can easily be carried out over period of weeks and its drug transportability may be examined, in addition to characterisation of the amadori products. A combination of ultrasensitive isothermal titration calorimetry, differential scanning calorimetry, spectroscopy and chromatography provides structure-property-energetics correlations which are important to obtain mechanistic aspects of drug recognition, conformation of the protein, and role of amadori products under conditions of glycation. The role of advance glycation end products is important in recognition of antidiabetic drugs. Further, the extent of glycation of the protein and its implication on drug transportability investigated by direct calorimetric methods enables unravelling mechanistic insights into role of functionality on drug molecules in the binding process, and hinderance in the recognition process, if any, as a result of glycation. It is possible that the drug binding ability of the protein under glycation conditions may not be adversely affected, or may even lead to strengthened ability. Rigorous studies on such systems with diverse functionality on the drug molecules is required which is essential in deriving guidelines for improvements in the existing drugs or in the synthesis of new molecular entities directed towards addressing diabetic conditions.

The blood-brain barrier (BBB) predominantly regulates insulin transport into and levels within the brain. The BBB is also an important site of insulin binding and mediator of insulin receptor (INSR) signaling. The insulin transporter is separate from the INSR, highlighting the important, unique role of each protein in this structure. After a brief introduction on the structure of insulin and the INSR, we discuss the importance of insulin interactions at the BBB, the properties of the insulin transporter and the role of the BBB insulin transporter in various physiological conditions. We go on to further describe insulin BBB signaling and the impact not only within brain endothelial cells but also the cascade into other cell types within the brain. We close with future considerations to advance our knowledge about the importance of insulin at the BBB.

The bone morphogenetic protein (BMP) system in the adrenal cortex plays modulatory roles in the control of adrenocortical steroidogenesis. BMP-6 enhances aldosterone production by modulating angiotensin (Ang) II-mitogen-activated protein kinase (MAPK) signaling, whereas activin regulates the adrenocorticotropin (ACTH)-cAMP cascade in adrenocortical cells. A peripheral clock system in the adrenal cortex was discovered and it has been shown to have functional roles in the adjustment of adrenocortical steroidogenesis by interacting with the BMP system. It was found that follistatin, a binding protein of activin, increased Clock mRNA levels, indicating an endogenous function of activin in the regulation of Clock mRNA expression. Elucidation of the interrelationships among the circadian clock system, the BMP system and adrenocortical steroidogenesis regulated by the hypothalamic-pituitary-adrenal (HPA) axis would lead to an understanding of the pathophysiology of adrenal disorders and metabolic disorders and the establishment of better medical treatment from the viewpoint of pharmacokinetics.