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Galanin, one of the most inducible neuropeptides, is widely present in developing brains, and its expression is altered by pathologic events (e.g., epilepsy, ischemia, and axotomy). The roles of galanin in brain development under both normal and pathologic conditions have been hypothesized, but the question of how galanin is involved in fetal and early postnatal brain development remains largely unanswered. In this study, using granule cell migration in the cerebellum of early postnatal mice (both sexes) as a model system, we examined the role of galanin in neuronal cell migration during normal development and after brain injury. Here we show that, during normal development, endogenous galanin participates in accelerating granule cell migration via altering the Ca 2+ and cAMP signaling pathways. Upon brain injury induced by the application of cold insults, galanin levels decrease at the lesion sites, but increase in the surroundings of lesion sites. Granule cells exhibit the following corresponding changes in migration: (1) slowing down migration at the lesion sites; and (2) accelerating migration in the surroundings of lesion sites. Experimental manipulations of galanin signaling reduce the lesion site-specific changes in granule cell migration, indicating that galanin plays a role in such deficits in neuronal cell migration. The present study suggests that manipulating galanin signaling may be a potential therapeutic target for acutely injured brains during development. SIGNIFICANCE STATEMENT Deficits in neuronal cell migration caused by brain injury result in abnormal development of cortical layers, but the underlying mechanisms remain to be determined. Here, we report that on brain injury, endogenous levels of galanin, a neuropeptide, are altered in a lesion site-specific manner, decreasing at the lesion sites but increasing in the surroundings of lesion sites. The changes in galanin levels positively correlate with the migration rate of immature neurons. Manipulations of galanin signaling ameliorate the effects of injury on neuronal migration and cortical layer development. These results shed a light on galanin as a potential therapeutic target for acutely injured brains during development., (Copyright © 2021 the authors.)

The neurohypophysial nonapeptides vasopressin (VP) and oxytocin (OT) modulate a broad range of cognitive and social activities. Notably, in amphibians, vasotocin (VT), the ortholog of mammalian VP, plays a crucial role in the control of sexual behaviors. Because several neurosteroids also regulate reproduction-related behaviors, we investigated the possible effect of VT and the OT ortholog mesotocin (MT) in the control of neurosteroid production. Double immunohistochemical labeling of frog brain sections revealed the presence of VT/MT-positive fibers in close proximity of neurons expressing the steroidogenic enzymes 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) and cytochrome P450 17alpha-hydroxylase/c17, 20-lyase (P450(C17)). High concentrations of VT and MT receptor mRNAs were observed in diencephalic nuclei containing the 3beta-HSD and P450(C17) neuronal populations. Exposure of frog hypothalamic explants to graded concentrations of VT or MT produced a dose-dependent increase in the formation of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone. The stimulatory effect of VT and MT on neurosteroid biosynthesis was mimicked by VP and OT, as well as by a selective V1b receptor agonist, whereas V2 and OT receptor agonists had no effect. VT-induced neurosteroid production was completely suppressed by selective V1a receptor antagonists and was not affected by V2 and OT receptor antagonists. Concurrently, the effect of MT on neurosteroidogenesis was markedly attenuated by selective OT and V1a receptor antagonists but not by a V2 antagonist. The present study provides the first evidence for a regulatory effect of VT and MT on neurosteroid biosynthesis. These data suggest that neurosteroids may mediate some of the behavioral actions of VT and MT.

In amphibians, thyrotropin-releasing hormone (TRH) is a potent stimulator of alpha-melanotropin (alpha-MSH) secretion, so TRH plays a major role in the neuroendocrine regulation of skin-color adaptation. We have recently cloned a third type of TRH receptor in Xenopus laevis (xTRHR3) that has not yet been characterized in any other vertebrate species. In the present study, we have examined the distribution of the mRNAs encoding proTRH and the three receptor subtypes (xTRHR1, xTRHR2, and xTRHR3) in the frog CNS and pituitary, and we have investigated the effect of background color adaptation on the expression of these mRNAs. A good correlation was generally observed between the expression patterns of proTRH and xTRHR mRNAs. xTRHRs, including the novel receptor subtype xTRHR3, were widely expressed in the telencephalon and diencephalon, where two or even three xTRHR mRNAs were often simultaneously observed within the same brain structures. In the pituitary, xTRHR2 was expressed selectively in the distal lobe, and xTRHR3 was found exclusively in the intermediate lobe. Adaptation of frog skin to background illumination had no effect on the expression of proTRH and xTRHRs in the brain. In contrast, adaptation of the animals to a white background provoked an 18-fold increase in xTRHR3 mRNA concentration in the intermediate lobe of the pituitary. These data demonstrate that, in amphibians, the effect of TRH on alpha-MSH secretion is mediated through the novel receptor subtype xTRHR3.

Ghrelin is a 28-amino acid n-octanoylated peptide recently isolated from the rat stomach as an endogenous ligand of the growth hormone secretagogue receptor. So far, the occurrence of ghrelin has not been investigated in submammalian vertebrates. In the present work, we have studied the anatomic distribution and biochemical characterization of ghrelin-like immunoreactivity in the brain and stomach of the frog Rana esculenta by using two distinct antisera directed against rat ghrelin. In the brain, sparse ghrelin-positive cells were detected in three nuclei of the diencephalon, namely the suprachiasmatic nucleus and the posterior tuberculum in the hypothalamus, and the posterodorsal aspect of the lateral nucleus in the thalamus. A few ghrelin-immunoreactive neurons were also found in the mesencephalon, i.e., in the pretoral gray and the anterodorsal tegmental nucleus. Ghrelin-containing fibers were widely distributed in the frog brain. In particular, diffuse networks of immunoreactive processes were observed in various regions of the telencephalon, including the medial pallium, the striatum, the nucleus of the diagonal band of Broca, the nucleus accumbens, and the amygdala. In the diencephalon, the magnocellular nucleus, the suprachiasmatic nucleus, the posterior tuberculum, and the ventrolateral and lateral thalamic nuclei were moderately to densely innervated with ghrelin-containing fibers. A moderate density of positive fibers was also found in different areas of the mesencephalon such as the nucleus of the medial longitudinal fasciculus, the pretoral gray, and the tegmentum. In the stomach, a few brightly immunofluorescent cells were detected in the mucosa. The distribution pattern and morphologic characteristics of ghrelin-containing cells in the stomach suggest that they correspond to endocrine cells. Reversed-phase high performance liquid chromatography analysis of frog brain and stomach extracts, combined with RIA detection, revealed that ghrelin-immunoreactive material eluted as a single peak with a retention time slightly shorter than that of synthetic rat ghrelin. The present data provide the first evidence that a ghrelin-related peptide is present in submammalian vertebrates. The occurrence of ghrelin-containing cells in the hypothalamus and the stomach mucosa suggests that, in amphibians, ghrelin may exert both neuroendocrine and endocrine activities., (Copyright 2002 Wiley-Liss, Inc.)

In the present study, we have investigated the distribution and biochemical characteristics of hypocretin (hcrt) -like immunoreactivity in the central nervous system (CNS) of the frog Rana ridibunda by using an antiserum directed against rat hcrt2. Immunoreactive cell bodies were only detected in four diencephalic nuclei, including the anterior preoptic area and the suprachiasmatic, magnocellular, and ventral hypothalamic nuclei. In contrast, hcrt2-immunoreactive fibers were widely distributed throughout the frog CNS. In particular, a high density of hcrt-positive fibers was detected in several areas of the telencephalon, including the olfactory bulb, the nucleus of the diagonal band of Broca, and the amygdala. A dense network of hcrt-containing fibers was observed in all thalamic and hypothalamic nuclei. A low to moderate density of immunoreactive fibers was also found in the mesencephalon, rhombencephalon, and spinal cord. Reversed-phase high performance liquid chromatography analysis of frog brain extracts revealed that hcrt2-immunoreactive material eluted as two peaks, the major one exhibiting the same retention time as synthetic rat hcrt2. The present data provide the first detailed mapping of the hcrt neuronal system in the CNS of a nonmammalian vertebrate. The occurrence of hcrt-containing cell bodies in the hypothalamus and the widespread distribution of hcrt-immunoreactive fibers throughout the brain and spinal cord suggest that, in amphibians, hcrts may exert neuroendocrine, neurotransmitter, and/or neuromodulator activities., (Copyright 2000 Wiley-Liss, Inc.)

We examined the distribution of the mRNAs encoding proTRH and the three TRH receptor subtypes (xTRHR1, xTRHR2, and xTRHR3) in the Xenopus laevis CNS and pituitary. A positive correlation was generally observed between the expression patterns of proTRH and xTRHR mRNAs. xTRHRs were widely expressed in the telencephalon and diencephalon, where two or even three xTRHR mRNAs were often simultaneously observed within the same brain structures. In the pituitary, xTRHR2 was selectively expressed in the distal lobe, and xTRHR3 was found exclusively in the intermediate lobe of white background-adapted animals, indicating that, in amphibians, the effect of TRH on α-melanotropin (α-MSH) secretion from melanotrope cells is mediated through the novel receptor subtype xTRHR3. [ABSTRACT FROM AUTHOR]