Download Inhibitory Regulation of Plasticity Across the Lifespan in the Rat Primary Auditory Cortex Book in PDF, ePub and Kindle
"Neuroplasticity refers to the brain’s ability to modify its connections and function in response to experience. This experience-dependent plasticity is necessary for the acquisition of new abilities during early development or in adult life, and plays a crucial role in recovery after a neurological injury. During early developmental epochs known as critical periods (CPs), passive experience alone can have profound and long-lasting effects in cortical sensory representations. In contrast, plasticity in the adult brain occurs almost exclusively in the context of perceptual learning (PL); i.e., the process whereby attention and repetition lead to long-lasting improvements in stimulus detection or sensory discrimination.Whether it occurs as a result of passive experience, PL, or other experimental interventions, cortical plasticity ultimately entails a change in activity patterns driven by a shift in the local levels of excitation and inhibition. And although cortical inhibitory interneurons constitute a clear minority compared to the number of excitatory neurons, they are instrumental in regulating both juvenile and adult experience-dependent plasticity. This thesis consists of three experimental studies that addressed critical and interrelated knowledge gaps regarding the inhibitory regulating mechanisms of experience-dependent plasticity, both in the context of changes in the environment and during PL. Using the rat primary auditory cortex (A1) as a model, we combined electrophysiological, anatomical, chemogenetic, and behavioral methodologies to address each study’s main hypotheses. In the first study we examined the role of inhibition in A1 plasticity across the lifespan. We found that reduced cortical inhibition in older adults was associated with an increased but poorly regulated plasticity when compared to younger adults. In older brains, however, changes elicited by auditory stimulation and training were rapidly lost, suggesting that such increased plasticity might be detrimental, as the older brains were unable to consolidate these changes. Importantly, increasing inhibition artificially with clinically available drugs restored the stability of sensory representations and improved the retention of plastic changes associated with PL.In the second study, we turned our attention to parvalbumin-positive (PV+) cells, the most common type of inhibitory neurons in the brain. Bidirectional manipulation of PV+ cell activity affected neuronal spectral and sound intensity selectivity, and, in the case of PV+ interneuron inactivation, was mirrored by anatomical changes in PV and associated perineuronal net expression. In addition, we showed that the inactivation of PV+ interneurons is sufficient to reinstate CP plasticity in the adult auditory cortex. In the third study, we investigated the role of PV+ cells in auditory PL. As previously reported in other cortical areas, training was associated with a transient downregulation of PV expression during early stages of training. We then examined the effects of prolonged PV+ cell manipulation throughout the training period. Our results suggest that, although reduced PV+ cell function may facilitate early training-related modifications in cortical circuits, a subsequent increase in PV+ cell activity is needed to prevent further plastic changes and consolidate learning. Taken together, our findings underscore the importance of sustained inhibitory neurotransmission in ensuring high fidelity discrimination of sensory inputs and in maintaining the stability of sensory representations. Our behavioral studies further suggest that such stability is necessary for the consolidation of complex skills that are built on basic sensory representations. Finally, the experimental work presented in this thesis also highlights the potential of pharmacological and chemogenetic approaches for harnessing cortical plasticity with the ultimate goal of aiding recovery from brain injury or disease"--