Mechanisms of Cortical Modification

Sensory experience at an early age is essential in determining the connectivity and the future capabilities of the cerebral cortex. A familiar example is learning foreign languages: so easy for children, so difficult for adults. A related form of developmental plasticity that can be studied in animals occurs in the visual cortex. Shortly after birth the visual cortex is so plastic that its connectivity can be modified by simple manipulation of sensory experience. During this plastic stage, closing one eye for a few hours (monocular deprivation) leads to the virtual disconnection of the closed eye. The effects of monocular deprivation, and the recovery following re-opening of the closed eye, are restricted to a brief postnatal critical period only. In adult animals, even prolonged monocular deprivation is without consequences. Remarkably, in humans, the critical period for visual cortical plasticity and the critical period for becoming fluent in a second language finish at about the same time, puberty. Thus, besides the obvious relevance of visual cortical plasticity to the development of visual capabilities, it seems likely that similar processes form the basis for some forms of learning and memory in other brain regions. The research in this lab is directed toward elucidating the basic mechanisms by which visual experience can modify cortical connections in the visual cortex, and how those mechanisms are regulated by age.

Concerning the cellular mechanisms for neural plasticity, there is mounting evidence that synaptic connections between neurons can be modified as they are used. As a general rule, effective connections are reinforced, whereas less effective connections are weakened. In the lab we study this type of modifications in slices of visual cortex. The slices can be kept alive for many hours and allow total control of neural activity, a key advantage when studying how neural activity modify the connectivity between neurons. Using this approach we have shown that a brief moment of intense activity strengthens the activated connections, whereas repetitive but weak activity weakens the connections. This type of use-dependent synaptic plasticity is ideally posed to account for the effects of experience on the wiring of the visual cortex. We expected a decline in this synaptic plasticity by the end of the critical period. It wasn’t that simple. Synapses in visual cortex retain the capability for modification well into adulthood, and well beyond the critical period. Indeed, in terms of plasticity, visual cortical slices prepared from young and older animals are indistinguishable. Seemingly, the lack of plasticity in the adult brain is not due to the absence of use-dependent synaptic modification. So, what makes the adult visual cortex so refractory to modification by experience? We propose that is due to the development of synaptic inhibition.

About a fifth of the neurons in the brain are inhibitory. These inhibitory neurons form a network that controls and regulates the propagation of activity throughout the brain. By doing so, the inhibitory network can also control plasticity, because synapses are modified by precise and specific patterns of activity. We have proposed that the maturation of these inhibitory networks is what reduces plasticity in the brain during development. According to this view, in the immature brain when inhibitory networks are not fully formed, neural activity flows freely, so to speak. Later on, as the animal ages and inhibition develops, the propagation of certain types activity (specifically, those that trigger plasticity) is tightly controlled. To test this hypothesis is the aim my research. All the evidence so far indicates that the increase in inhibition causes the end of the critical period. This is a very exciting possibility. It will mean that by studying the regulation of synaptic inhibition we are likely to gain an understanding of how brain plasticity declines with aging. In addition it could give some hope for restoring some plasticity in adult brains. If our hypothesis is correct, plasticity should be enhanced by reducing inhibition –a tricky and difficult maneuver to perform in a living brain, but doable nevertheless.