The role of the cerebellar cortex in motor learning was investigated by comparing the paramedian lobule of adult rats given difficult acrobatic training to that of rats that had been given extensive physical exercise or had been inactive. The paramedian lobule is activated during limb movements used in both acrobatic training and physical exercise. Acrobatic animals had greater numbers ofsynapses per Purkin e cell than animals from the exercise or inactive groups. No significant difference in synapse number or size between the exercised and inactive groups was found. This indicates that motor learning required of the acrobatic animals, and not repetitive use of synapses during physical exercise, generates new synapses in cerebellar cortex. In contrast, exercise animals had a greater density ,f blood vessels in the molecular layer than did either the acrobatic or inactive animals, suggesting that increased Synaptic activity elicited compensatory angiogenesis.Although many aspects of experience can alter synaptic connectivity (1-5), it has-been difficult'to relate unequivocally these changes to learning and memory because the morphological effects of leaning could not be isolated from those of behaviors. required to perform the task. For example, maze training (3) and forelimb reach-training (5) can alter neuronal morpholoy, but substantia trepetition of movements is required fo arning these, tasks'. Thus it is not possible to ascrib~e te morphological effects to learning per se.The cerebellar cortex may be particularly appropriate for testing hypotheses about synaptic plasticity because empirical evidence has implicated cerebellar cortex in motor skill learning (6,7,36), and there is some indication that synapse formation underlies cerebellar cortical learning, as suggested by dendritic-field changes in Purkinje cells of rodents and monkeys exposed to challenging. sensory-motor environments (8-10). Synaptogenesis in adult rat cerebellar cortex also occurs when afferents are cut (11,12). Furthermore, theorists have noted the suitability of cerebellar cortex for motor learning, with its convergence of two afferent systems conveying extensive somatic and cerebral state information upon the Purkinje cell, a single-output neuron that modulates motor activity (13)(14)(15)(16)(17).The results of the present study show that learning, as opposed to the motor activity necessary for learning a complex motor task, is responsible for synapse formation in the cerebellar cortex. We report a dissociation oflearning and motor activity, in which animals provided with complex visuomotor learning and minimal motor activity (acrobatic training)-form substantial numbers of new synapses in cerebellar cortex, whereas animals given extensive locomotor exercise with minimal opportunities for learning (repetitive exercise) formed new blood vessels but formed no more new synapses than animals in an inactive control group. MATERIAL AND METHODSAnimals and Training. Thirty-eight adult Long-Evans hooded female rats, kept in small groups...

This study compared the morphology of cerebellar cortex in adult female rats exposed for 1 month to repetitive exercise, motor learning, or an inactive condition. In the exercise conditions, rats that were run on a treadmill or housed with access to a running wheel had a shorter diffusion distance from blood vessels in the molecular layer of the paramedian lobule when compared to rats housed individually or rats that participated in a motor skill learning task. Rats taught complex motor skills substantially increased the volume of the molecular layer per Purkinje neuron and increased blood vessel number sufficiently to maintain the diffusion distance. These results dissociate angiogenesis associated with increased neuropil volume (as seen in the motor learning group) from angiogenesis associated with increased metabolic demands (as seen in the exercise groups). While the volume fraction of mitochondria did not differ among groups, the mitochondrial volume fraction per Purkinje cell was significantly increased in the motor skill rats. This appears to parallel the previously reported increase in synapses and associated neuropil volume change.

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Rats reared from weaning in a complex environment have an increase in 1) glial surface area, 2) capillary volume, and 3) the number of synapses, per neuron. In that paradigm it has not been possible to determine whether the glial increase more closely correlates with the increase in synaptic numbers or with angiogenesis. More recently we have found that rats that exercised had an increase in the density of capillaries without an increase in the synaptic numbers, whereas rats that learned new motor skills had a greater number of synapses per neuron without an increase in the density of capillaries. Those findings provided the opportunity to investigate whether changes in glial volume in the cerebellum correspond to changes in the number of synapses or in capillary volume. Glial area fraction estimates were obtained using point counts on electron micrographs from the previous studies. The skill learning group had a greater volume of molecular layer per Purkinje cell, and also a greater volume of glia per Purkinje cell, than rats in either an inactive group or rats in two exercise groups. No significant differences were found in glial volume per synapse and glial volume per capillary across groups, although there was a tendency for glial volume per capillary to be lower in the exercise groups. The data indicate that glial volume correlates with synaptic numbers and not with capillary density.

Glucocorticoids (GCs) are hormones secreted by the adrenal glands as an endocrine response to stress. Although the main purpose of GCs is to restore homeostasis when acutely elevated, animal studies indicate that chronic exposure to these hormones can cause damage to the hippocampus. This is indicated by reductions in hippocampal volume, and changes in neuronal morphology (i.e.., decreases in dendritic length and number of dendritic branch points) and ultrastructure (e.g., smaller synapse number). Smaller hippocampal volume has been also reported in humans diagnosed with major depressive disorder or Cushing's disorder, conditions in which GCs are endogenously and chronically elevated. Although a number of studies considered neuron loss as the major factor contributing to the volume reduction, recent findings indicated that this is not the case. Instead, alterations in dendritic, synaptic and glial processes have been reported. The focus of this paper is to review the GCs effects on the cell number, dendritic morphology and synapses in an effort to better understand how these changes may contribute to reductions in hippocampal volume. Taken together, the data from animal models suggests that hippocampal volumetric reductions represent volume loss in the neuropil, which, in turn, under represent much larger losses of dendrites and synapses.

Behavioral manipulations such as housing in an enriched environment have been shown to increase brain weight and visual cortical thickness. The present study was designed to test whether skill learning or repetitive movements can alter the thickness of the motor cortex. One group of 6-mo-old Long-Evans female rats learned motor skills on an obstacle course that increased in difficulty over training and required balance and coordination. A second group ran voluntarily in exercise wheels attached to their home cage but had little opportunity for skill learning. The third group was handled daily but received no opportunity for learning or exercise. Each condition lasted 26-29 d. The skill-learning and exercise conditions had greater heart weight, and the exercise condition had greater adrenal gland weights than controls. The thickness of the motor cortex was measured in four coronal planes between −2.33 mm to −0.3 mm from bregma. Regions of interest that corresponded to published maps of forelimb and hind-limb representations were analyzed together. Rats in the skill-learning condition had significantly thicker medial cortical areas in the two anterior planes (−0.8 and −0.3 mm from bregma). These regions correspond to previously mapped hind-limb representations. The exercise group had greater thickness of the medial region at −0.8 mm from bregma. Cortical thickness in all conditions varied significantly along the medial to lateral axis. For both treatments, the effects were restricted to medial and anterior regions of interest rather than posterior or lateral regions of interest. The results indicate that robust exercise, in addition to skill learning, is capable of altering the thickness of the motor cortex, but that the effects are restricted rather than distributed within the regions studied.

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Individuals with clinical disorders associated with elevated plasma glucocorticoids, such as major depressive disorder and Cushing's syndrome, are reported to have smaller hippocampal volume. To understand how the hippocampus responds at the cellular and subcellular levels to glucocorticoids and how such changes are related to volume measures, we have undertaken a comprehensive study of glucocorticoid effects on hippocampal CA3 volume and identified elements in the neuropil including astrocytic volume and cell and synapse number and size. Male Sprague-Dawley rats were injected with corticosterone (40 mg/kg), the primary glucocorticoid in rodents, or vehicle for 60 days. The CA3 was further subdivided so that the two-thirds of CA3 (nearest the dentate gyrus) previously shown to be vulnerable to corticosterone could be analyzed as two separate subfields. Corticosterone had no effect on neuropil volume or glial volume in the proximal subfield but caused a strong tendency for astrocytic processes to make up a larger proportion of the tissue and for volume of tissue made of constituents other than glial cells (primarily neuronal processes) to be smaller in the middle subfield. Within the neuropil, there were no cellular or subcellular profiles that indicated degeneration, suggesting that corticosterone does not cause prolonged damage. Corticosterone did not reduce cell number or cell or nonperforated synapse size but did cause a pronounced loss of synapses. This loss occurred in both subfields and, therefore, was independent of volume loss. Together, the findings suggest that volume measures can underestimate corticosterone effects on neural structure.