Regulation of experience dependent plasticity in the rodent developing visual cortex: cholinergic modulation of upward homeostasis
Creators: name: Bottorff, Juliet
Publisher: name: Brandeis University
Year: 2023
Subjects: acetylcholine
experience dependent plasticity
homeostasis
neuromodulation

description: Two types of experience dependent plasticity mechanisms are essential for proper learning and information storage in neocortical circuits. Hebbian mechanisms are correlation based and generate positive feedback, but they are inherently unstable and can lead to runaway excitation and loss of information when left unchecked. Homeostatic mechanisms provide necessary stability by generating negative feedback and adjusting neuronal activity bidirectionally around a set point, thus keeping activity in a functional range. Recently, behavioral states have emerged as important regulators of some forms of homeostatic plasticity, but how this regulation occurs remains unknown. Monocular deprivation in rats first induces a Hebbian-like drop in neural activity in deprived visual cortex neurons, followed by a slow homeostatic rebound back to baseline termed firing rate homeostasis; this upward firing rate homeostasis is gated by active wake behavioral states (Hengen et al., 2016). Subsequent eye reopening then induces a Hebbian-like overshoot in neural activity, followed by a homeostatic rebound back to baseline termed downward firing rate homeostasis, which is gated by sleep states (Torrado Pacheco et al., 2021). I began my thesis work by asking if the Hebbian phases of each of these paradigms were similarly gated by sleep/wake states; I found that, unlike upward and downward firing rate homeostasis, the early drop in activity after monocular deprivation and the early overshoot in activity after subsequent eye reopening both occur independently of sleep/wake state. Because different behavioral states consist of distinct neuromodulatory tone, and neuromodulators are key regulators of many forms of plasticity, I hypothesized that neuromodulators may underlie the behavioral state gating of homeostatic plasticity. I asked if acetylcholine, a neuromodulator prominent during active wake states, is necessary for active wake-gated upward firing rate homeostasis. I found that inhibiting cholinergic input to visual cortex prevents the expression of firing rate homeostasis after monocular deprivation; further, it disrupts the induction of two forms of cellular homeostatic plasticity known to accompany upward firing rate homeostasis. Inhibiting cholinergic neurons caused a partial occlusion of synaptic scaling up in visual cortex, and it caused a significant decrease in intrinsic excitability in visual cortex neurons only when paired with visual cortex activity suppression. This latter effect could help explain why inhibiting cholinergic input prevents firing rate homeostasis after monocular deprivation. Finally, I used the photoconvertible fluorescent protein CaMPARI2 to measure firing rate homeostasis after monocular deprivation in mice and rats, and I asked if this tool would allow for more efficient study of how neuromodulators regulate behavioral state-dependent plasticity. However, I found unexplained interaction effects of clozapine N-oxide and CaMPARI2 that limit the usefulness of this tool to further study this regulation. Regardless, the results presented in this thesis further our understanding of how behavioral states regulate experience dependent plasticity and provide several avenues for future research on this regulation.