James E. Black

Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning.

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.

Complex experience promotes capillary formation in young rat visual cortex

The metabolic support of neural plasticity was examined by comparing cerebral vasculature of weanling rats reared in complex environments (EC) to littermates reared individually (IC) or socially in pairs (SC). EC rats have a thicker occipital cortex, more synaptic contacts per neuron and larger dendritic arbors compared to SC or IC rats, potentially increasing local metabolic demands on microvasculature. Capillaries of EC rats were closer together than those of SC or IC rats and potentially filled a greater fraction of cortex with blood. The closer capillary spacing in young EC rats suggests compensatory angiogenesis in response to increased metabolic demand.

Direct evidence that complex experience increases capillary branching and surface area in visual cortex of young rats

Rats housed in complex environments with toys and other rats generate new synapses, and the expanding neuropil tends to spread apart existing blood vessels. Previous work demonstrated that weanling rats kept in complex environments had more closely packed capillaries, suggesting that new capillaries had sprouted into the newly added neuropil. The present study directly investigates the issue of new branching by using india ink perfusions of weanling rats kept for 30 days in a complex environment (EC), paired in standard caging (SC), or individual cages (IC) to examine the density of capillary branch points and the capillary surface area per unit tissue volume. EC rats had a greater density of branch points than the SC and IC littermates, a finding consistent with increased capillary sprouting. Capillary surface area per unit tissue volume and the number of branch points per unit of capillary surface area were also higher for EC rats. This suggests that blood vessels of EC rats branch off more often than those of animals kept in more standard conditions, and provides further evidence that complex experience can increase angiogenesis in cerebral cortex of postweanling rats.

Progressive failure of cerebral angiogenesis supporting neural plasticity in aging rats.

Previous work has demonstrated substantial formation of new synapses and capillary branches in visual cortex of young rats provided with complex experience. Synaptogenesis appears greatly weakened in old rats, however, perhaps because of an age-associated impairment of metabolic support. We have examined capillaries in visual cortex from eight 14-month-old and nine 24-month-old rats that had been kept for 50 days in either a complex environment with toys and other rats or in the standard laboratory condition they had been raised in. In spite of tissue expansion that increased cortical thickness and spread apart existing blood vessels in 14-month-old rats that received complex experience, the density of capillaries was not affected. These results indicate that new capillaries infiltrated the expanding tissue. These rats also had significantly more small-diameter capillaries, possibly reflecting the immaturity of new vessels and effectively reducing the maximum amount of blood available to the tissue. Similar but nonsignificant trends were observed in the 24-month-old animals given complex experience. These results suggest that angiogenesis, while it does occur, is substantially impaired in middle-aged animals, and a failure of angiogenesis in old rats may explain their reduced capacity for synaptogenesis.

Capillary and mitochondrial support of neural plasticity in adult rat visual cortex

Young adult rats (60 days old) were placed in complex environments (EC) or kept in individual cages (IC) for 10, 30, or 60 days. Previously reported findings in these same animals of synaptogenesis, decreased neuronal density, and increased cortical thickness in the EC animals demonstrated that cortical volume substantially expanded after 30 days. Such expansion would have spread apart existing capillaries and mitochondria, thereby diluting metabolic support. However, capillary spacing and mitochondrial volume fraction were maintained in these EC animals after 30 days, suggesting that new capillaries and mitochondria had infiltrated the tissue. Furthermore, many small vessels appeared after 10 days of complex experience, followed by expansion in vessel size until vessels from rats in EC for 60 days were larger than those from rats in IC for 60 days. The findings of constant vessel spacing in the face of expanding tissue volume, along with a set of small vessels that subsequently increased in size, suggest that small-sized new vessels were introduced in EC cortex by 10 days but had not matured in size until after 30 days. The results indicate that young adult rats can generate new capillaries and mitochondria in response to increased metabolic demands, but in a less vigorous fashion than in previously described weanling animals.

Astrocyte hypertrophy in the dentate gyrus of young male rats reflects variation of individual stress rather than group environmental complexity manipulations

Glial hypertrophy is associated with synaptogenesis in visual cortex and with stress-induced damage in the hippocampus. This study examined astrocytes in the dentate gyrus of male weanling rats exposed to complex or standard laboratory environments. No group differences in astrocytic surface density were observed, as expected in this brain region where group differences in synaptogenesis in male rats are reportedly minimal. Similarly, no group differences in adrenal weight were observed. Across all treatment groups, however, a significant positive correlation (r = 0.57) between adrenal weight and surface density of astrocytic processes was found. Considerable variation in responses of individual rats to their environments occurs in both the complex and the laboratory cage environments, and animals responding poorly may have had heavier adrenals and greater astrocyte reactivity in the dentate gyrus. Thus astrocyte hypertrophy in the dentate gyrus reflects the stress history of the individual rat and not any differential effects of rearing in a complex or a laboratory cage environment.

2 – Developmental Approaches to the Memory Process*

Publisher Summary Tinbergen (1951) suggested that the question about why this animal behaves this way, requires four related answers: the immediate causal control of the behavior, the animals developmental history, the behaviors contribution to survival, and the evolution of the species trait. In asking why the animal learns and remembers, scientists concentrated primarily on the first answer, or the immediate causes, both biological and psychological. In contrast, this chapter focuses on the developmental perspective set in the context of some ethological and evolutionary concerns. In the last half of the nineteenth century, scientists in fields ranging from histology to psychiatry were proposing that memory and development were intimately linked to subtle movements of neural processes. Because synapses were not visible with light microscopy, these connections between neurons became the focus of much speculation. The chapter largely restricts discussion to data indicating changes in numbers of synapses, rather than their size or shape. Changes in structural characteristics of existing synapses that might also be involved in memory storage have been reviewed elsewhere.

Chapter 2 – Developmental Approaches to the Memory Process

Publisher Summary This chapter reviews the application of developmental approaches for explaining the processes of learning and memory. In the second half of 19th century, scientists from different fields, ranging from histology to psychiatry, proposed that memory and development were intimately linked to subtle changes in neural processes. It was suggested that this formation of new synaptic connections between neurons due to learning and the frequent use of a synapse might produce growth similar to that produced by exercising a muscle, thereby strengthening pre-existing connections. Both theories assumed that the structural plasticity, found during the development process, is present in adulthood as well. The neocortex retains considerable structural plasticity in response to differential housing into adulthood, as is expected for experience-dependent mechanisms designed for learning. Studies on humans, primates, and other animals have shown that human brain can reorganize the stored information in an experience-dependent fashion, validating the continued use of animal models of experience-dependent plasticity. This evidence validates the learning-induced changes in the number of synapses, glial cell morphology, and neuron-glia communication in many brain regions of both young and mature animals. Such effects are seen across a number of species, including non-mammalian, and across types of experience, from light deprivation to maze learning; and are correlated with changes in neuronal function and behavior. This suggests that evolution may not have established two separate mechanisms for developmental plasticity and memory. This chapter proposes that learning results in the formation of new synapses as well as new neurons that are involved in the permanent encoding of the memory as alterations in the circuitry of the brain systems in which the memory is stored.

Metabolic Support of Neural Plasticity: Implications for the Treatment of Alzheimer’s Disease

Imagine a “magic bullet” for Alzheimer’s Disease, i.e., a therapy that would do more than just halt the degeneration--this novel treatment would restore the atrophied neocortex and perhaps even replace some of the lost information. Such a glamorous cure for Alzheimer’s disease carries with it a hidden requirement, one that has been relatively neglected in this area of research. The addition of cortical tissue late in life will impose new metabolic demands for synthesis of synaptic connections and the associated dendritic and axonal material. In addition, the volume expansion will tend to dilute metabolic support as the existing capillaries are spread apart. For these reasons any significant restoration of functional cortex will have to include some improvement in its metabolic support.