Neuronal plasticity is a central theme of modern neurobiology, from cellular and molecular mechanisms of synapse formation in Drosophila to behavioural recovery from strokes in elderly humans. Although the methods used to measure plastic responses differ, the stimuli required to elicit plasticity are thought to be activity-dependent. In this article, we focus on the neuronal changes that occur in response to complex stimulation by an enriched environment. We emphasize the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.

Neural consequences of environmental enrichment.

Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)

Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity

We explore the extent to which neocortical circuits generalize, i.e., to what extent can neocortical neurons and the circuits they form be considered as canonical? We find that, as has long been suspected by cortical neuroanatomists, the same basic laminar and tangential organization of the excitatory neurons of the neocortex is evident wherever it has been sought. Similarly, the inhibitory neurons show characteristic morphology and patterns of connections throughout the neocortex. We offer a simple model of cortical processing that is consistent with the major features of cortical circuits: The superficial layer neurons within local patches of cortex, and within areas, cooperate to explore all possible interpretations of different cortical input and cooperatively select an interpretation consistent with their various cortical and subcortical inputs.

Neuronal circuits of the neocortex

Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

Experience-dependent structural synaptic plasticity in the mammalian brain.

How Does the Brain Solve Visual Object Recognition

The number of neurons, glia, and synapses in the visual cortex of adult macaque monkeys has been estimated by stereological methods. The data is presented separately for 13 sublaminae. For the total cortical thickness, the average numerical density of neurons is approximately 120,000 per mm3 of tissue. This density increases and decreases in the different sublaminae in the direction that one would expect from the classical descriptions of Nissl-stained material (e.g., 137,000/mm3 in IVC alpha; 211,000/mm3 in IVC beta). There are about 200,000 neurons under 1 mm2 or cortical surface: 28% are in layers I-III, 45% are in layer IV, and 27% are in layers V and VI. The total number in area 17 of one hemisphere is close to 160,000,000. For the total cortical thickness the numerical density of synapses is 276,000,000 per mm3 of tissue. Laminae with higher neuronal densities tend to have higher synaptic densities but the correlation is not perfectly concordant. Moreover, the changes in synaptic densities are not as great as those in neuronal densities so that laminae with higher neuronal densities have a lower synapse to neuron ratio and laminae with lower neuronal densities have a higher synapse to neuron ratio. For the total cortical thickness this ratio is 2,300 synapses per neuron (1,400 in layer IVC beta and 2,800 in layers II and III). There are 478 million synapses under 1 mm2 cortical surface: 40% are in layers I-III, 35% are in layer IV, and 25% are in layers V and VI. The numerical densities of astrocytes, oligodendrocytes, and microcytes are 38,000, 17,000, and 4,000 per mm3, respectively. The overall glia/neuron ratio is 0.49.

A laminar analysis of the number of neurons, glia, and synapses in the visual cortex (area 17) of adult macaque monkeys

The number of synapses per unit volume of tissue (NV) has been estimated in individual laminae of the binocular and monocular regions of area 17 in six adult cats by using a method of size-frequency distribution. Separate estimates were obtained for RA synapses (containing round vesicles associated with asymmetric membrane differentiations) and for FS synapses (containing flat vesicles associated with symmetric membrane differentiations). For the total cortical thickness, the NV of all synapses is not statistically different between binocular (286 million per mm1(3] and monocular (281 million) regions, nor is it different between the two regions for any of the laminae. Eighty-four percent of synapses are of the RA type. Of those, 79% are found on dendritic spines, 21% on dendritic trunks, 0.1% on somata. FS synapses represent 16% of the total, with 31% of them on spines, 62% on dendritic trunks, and 7% on somata. The ratio of RA to FS synapses is kept relatively constant throughout the layers. A two-way analysis of variance shows no difference in the NV of either RA or FS synapses in the two regions nor in the NV or RA synapses between cats. It does, however, clearly demonstrate (p less than 0.001) interindividual differences for FS synapses. These variations between individual cats may be due to differences in age, breed, or environmental factors. In contrast to the relative uniformity of the NV of synapses between regions, the number of each type under 1 mm2 of cortical surface is 33% higher in the binocular region. This is due mainly to the greater thickness of the binocular region.

A laminar analysis of the number of round‐asymmetrical and flat‐symmetrical synapses on spines, dendritic trunks, and cell bodies in area 17 of the cat

In order to study the mechanisms of synaptogenesis in the rat cerebellar cortex, a library of monoclonal antibodies has been generated against proteins of the isolated synapse. One recognizes a glycosylated 38 kDa protein that is concentrated in the synaptic vesicle fraction and resembles synaptophysin biochemically in its molecular weight, charge, and pattern of glycosylation. In the adult cerebellar cortex, the antisynaptophysin(mabQ155) immunoreactivity is codistributed with synapses. Immunoreactivity is strongest in the molecular layer where punctate deposits of reaction product outline the Purkinje cell dendrites. Discrete small profiles, consistent with the distribution of basket cell axon terminals, surround the Purkinje cells, and in the granular layer the synaptic glomeruli are intensely stained. There is no immunoreactivity in the white matter axon tracts. Electron microscope immunocytochemistry confirms the synaptic location of the antigen and suggests that the reaction product is associated with synaptic vesicles. Both round and flat vesicle populations are immunoreactive. Antisynaptophysin(mabQ155) has been used to follow synaptogenesis in the developing rat cerebellum. In the newborn rat (P0), despite the paucity of synapses, there is some specific immunoreactivity, especially in the subcortical white matter. Electron microscopy shows that the antigenicity is associated with vesicles within growth cones, filopodia, and immature axon profiles. During development, antisynaptophysin immunoreactivity increases progressively, along with the maturing cell populations, for both the granule cell-Purkinje cell and the mossy fiber-granule cell synapses. Quantitative biochemical analysis confirms the cytochemical results. These data suggest that neuronal growth cones express a synapse-specific antigen before complete morphological synapses are present.

Synaptophysin expression during synaptogenesis in the rat cerebellar cortex

The surface area of the striate cortex and the thickness of its laminae were measured in a series of newborn, 3-month, 6-month, and adult macaque monkeys. The numerical densities (Nv) of neurons and synapses were measured in individual laminae. The total numbers of neurons and synapses in the striate cortex of one hemisphere were derived from these measures. Normal monkeys were compared at 3 months and 6 months of age to animals having been reared from birth with a monocular eyelid suture. No significant differences were observed between normal and monocularly deprived monkeys. The perceptual deficits and physiological abnormalities that have been reported in monocularly deprived monkeys do not appear to result from a reduction in the amount of neural circuitry in the striate cortex. The combined data from these groups, however, demonstrated several developmental changes. Cortical thickness increased from birth to 6 months and diminished to near-newborn values in the adult. The 6-month cortex was 19% thicker than that of the adult. This overshoot was greatest in layers II and III, which were 43% thicker at 6 months. Cortical surface area demonstrated a similar trend, being 23% greater at 6 months, but the differences were not statistically significant. The Nv of neurons decreased from birth to 6 months and increased to near-newborn values in the adult. The 6-month Nv was 30% less than that of adults and the greatest changes were seen in layers II and III where the Nv was 38% less than adult values. The total number of neurons in the striate cortex of one hemisphere was 16% less in adults than in newborn animals, but statistically significant neuron losses were limited to layers I, II, IVC alpha, V, and VI. The Nv of synapses increased from birth to 6 months and diminished to near-newborn values in the adult. The 6-month overshoot was 34% for the total cortex and 41% for layers I-III. The total number of synapses in the striate cortex was 95% greater at 6 months than in the adult. In layers I-III the synapses were 130-155% more numerous at 6 months. These data demonstrate an increase in neuronal connectivity in the striate cortex from birth to 6 months, especially in layers I-III, and a subsequent decrease in the adult.

Postnatal changes in the number of neurons and synapses in the visual cortex (area 17) of the macaque monkey: a stereological analysis in normal and monocularly deprived animals.

Marc Colonnier

Papers

A laminar analysis of the number of neurons, glia, and synapses in the visual cortex (area 17) of adult macaque monkeys

A laminar analysis of the number of round‐asymmetrical and flat‐symmetrical synapses on spines, dendritic trunks, and cell bodies in area 17 of the cat

Synaptophysin expression during synaptogenesis in the rat cerebellar cortex

Postnatal changes in the number of neurons and synapses in the visual cortex (area 17) of the macaque monkey: a stereological analysis in normal and monocularly deprived animals.

Monoclonal antibodies reveal sagittal banding in the rodent cerebellar cortex