Teen binge drinking is associated with low frontal white matter integrity and increased risk of alcoholism in adulthood. This neuropathology may result from alcohol exposure or reflect a pre-existing condition in people prone to addiction. Here we used rodent models with documented clinical relevance to adolescent binge drinking and alcoholism in humans to test whether alcohol damages myelinated axons of the prefrontal cortex. In Experiment 1, outbred male Wistar rats self-administered sweetened alcohol or sweetened water intermittently for 2 weeks during early adolescence. In adulthood, drinking behavior was tested under nondependent conditions or after dependence induced by 1 month of alcohol vapor intoxication/withdrawal cycles, and prefrontal myelin was examined 1 month into abstinence. Adolescent binge drinking or adult dependence induction reduced the size of the anterior branches of the corpus callosum, i.e., forceps minor (CC FM ), and this neuropathology correlated with higher relapse-like drinking in adulthood. Degraded myelin basic protein in the gray matter medial to the CC FM of binge rats indicated myelin was damaged on axons in the mPFC. In follow-up studies we found that binge drinking reduced myelin density in the mPFC in adolescent rats (Experiment 2) and heavier drinking predicted worse performance on the T-maze working memory task in adulthood (Experiment 3). These findings establish a causal role of voluntary alcohol on myelin and give insight into specific prefrontal axons that are both sensitive to alcohol and could contribute to the behavioral and cognitive impairments associated with early onset drinking and alcoholism.

Naturally occurring cell death is essential to the development of the mammalian nervous system. Although the importance of developmental cell death has been appreciated for decades, there is no comprehensive account of cell death across brain areas in the mouse. Moreover, several regional sex differences in cell death have been described for the ventral forebrain and hypothalamus, but it is not known how widespread the phenomenon is. We used immunohistochemical detection of activated caspase-3 to identify dying cells in the brains of male and female mice from postnatal day (P) 1 to P11. Cell death density, total number of dying cells, and regional volume were determined in 16 regions of the hypothalamus and ventral forebrain (the anterior hypothalamus, arcuate nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, and ventromedial nucleus of the hypothalamus; the basolateral, central, and medial amygdala; the lateral and principal nuclei of the bed nuclei of the stria terminalis; the caudate-putamen; the globus pallidus; the lateral septum; and the islands of Calleja). All regions showed a significant effect of age on cell death. The timing of peak cell death varied between P1 to P7, and the average rate of cell death varied tenfold among regions. Several significant sex differences in cell death and/or regional volume were detected. These data address large gaps in the developmental literature and suggest interesting region-specific differences in the prevalence and timing of cell death in the hypothalamus and ventral forebrain.

Several sex differences in the nervous system depend on differential cell death during development in males and females. The anti-apoptotic protein, Bcl-2, promotes the survival of many types of neurons during development and in response to injury. To determine whether Bcl-2 might similarly control cell death in sexually dimorphic regions, we compared neuron number in wild-type mice and transgenic mice overexpressing Bcl-2 under the control of a neuron-specific promoter. Three neural areas were examined: the spinal nucleus of the bulbocavernosus (SNB), in which neuron number is greater in males; the retrodorsolateral nucleus (RDLN) of the spinal cord, which exhibits no sex difference in neuron number; and the anteroventral periventricular nucleus (AVPV) of the hypothalamus, in which both overall cell density and the number of tyrosine hydroxylase immunoreactive (TH-ir) neurons are greater in females. Bcl-2 overexpression significantly increased SNB cell number in females, overall cell density of AVPV in males, and RDLN cell number in both sexes. Bcl-2 overexpression did not alter the number of TH-ir neurons in AVPV of males or females. These findings indicate that Bcl-2 can regulate sexually dimorphic cell number in the brain and spinal cord and suggest that Bcl-2 may mediate effects of testosterone on cell survival during neural development. In contrast to the regulation of overall cell density in AVPV, the sex difference in TH cell number apparently is not caused by a Bcl-2-dependent mechanism.

The accessory optic system of Rana pipiens was investigated by autoradiographic, horseradish peroxidase, and Golgi techniques, revealing a complexity of neuroanatomical organization previously unrecognized. Retinal afferents project to the nucleus of the basal optic root (nBOR) via a primary bundle and more diffuse, medial bundle of optic axons, both of which contain large- and small-diameter fibers. At least six types of retinal ganglion cell contribute to the basal optic root (BOR), including giant ganglion cells, two intermediate-sized ganglion cell types, small ganglion cells, and two types of displaced ganglion cell. The major retinal projection is contralateral, but a small, ipsilateral component also exists. Afferents from neurons which are postsynaptic to the thalamic retinal terminal fields also reach nBOR. Four distinct cell types were identified within the terminal field of nBOR: stellate neurons (63%), amacrine cells (19%), elongate neurons (14%), and large ganglionic neurons (4%). Both stellate and amacrine cells appear to be intrinsic neurons, while elongate and ganglionic neurons constitute the efferent neuron population of nBOR. In addition, cells which lie medial to the terminal field, pyriform and commissural neurons, send dendrites into nBOR. Pyriform neurons project to the nucleus of the medial longitudinal fasciculus (nMLF) and cranial nerve nuclei III and IV, while commissural neurons project to the contralateral nBOR. Large reticular neurons of the nMLF also send dendrites into nBOR. Efferent projections from nBOR were observed in the large-celled pretectal nucleus and in nucleus lateralis profundus. A second major projection originates from the peri-nBOR region and is associated with the oculomotor system and with the nMLF. Efferent projections from the nMLF to the vestibular nuclei and to the rostral spinal cord were also observed, as well as projections which reach the brainstem from the large-celled pretectal nucleus, the posterior thalamic and anterior mesencephalic central gray.

A direct pathway from the retina to the dorsal raphe nucleus (DRN) has been demonstrated in both albino rats and Mongolian gerbils. Following intraocular injection of cholera toxin subunit B (CTB), a diffuse stream of CTB‐positive, fine‐caliber optic axons emerged from the optic tract at the level of the pretectum/anterior mesencephalon. In gerbils, CTB‐positive axons descended ventromedially into the periaqueductal gray, moving caudally and arborizing extensively throughout the DRN. In rats, the retinal‐DRN projection comprised fewer, but larger caliber, axons, which arborized in a relatively restricted region of the lateral and ventral DRN. Following injection of CTB into the lateral DRN, retrogradely labeled ganglion cells (GCs) were observed in whole‐mount retinas of both species. In gerbils, CTB‐positive GCs were distributed over the entire retina, and a nearest‐neighbor analysis of CTB‐positive GCs showed significant regularity (nonrandomness) in their distribution. The overall distribution of gerbil GC soma diameters ranged from 8 to 22 μm and was skewed slightly towards the larger soma diameters. Based on an adaptive mixtures model statistical analysis, two Gaussian distributions appeared to comprise the total GC distribution, with mean soma diameters of 13 (SEM ±1.7) μm, and 17 (SEM ±1.5) μm, respectively. In rats, many fewer CTB‐positive GCs were labeled following CTB injections into the lateral DRN, and nearly all occurred in the inferior retina. The total distribution of rat GC soma diameters was similar to that in gerbils and also was skewed towards the larger soma diameters. Major differences observed in the extent and configuration of the retinal‐DRN pathway may be related to the diurnal/crepuscular vs. nocturnal habits of these two species. J. Comp. Neurol. 414:469–484, 1999. © 1999 Wiley‐Liss, Inc.