Behavioral State Gating of Neuroplasticity: The Role of State-Specific Neuromodulators in Firing Rate Homeostasis - Project Summary
It is clear that sleep and wake states have a profound influence on cortical plasticity and they are
necessary for many forms of functional learning and memory; they also represent distinct brain states, during
which sensory drive, neuromodulation, and activity patterns are dramatically different. Given that
neuromodulators are strong regulators of many forms of plasticity and cortical activity patterns, this suggests
that sleep or wake, via specific neuromodulators, may select for distinct plasticity mechanisms. This state-
specific selection of plasticity mechanisms has significant potential benefits; for example, it is critical that
Hebbian (positive feedback-mediated) and homeostatic (negative feedback-mediated) plasticity mechanisms
work together efficiently to keep complex brain circuits plastic and stable, and to avoid cataleptic or epileptic
states. The fact that the two types of plasticity have some of the same molecular effectors implies they could
interfere with each other if not appropriately segregated. Indeed, many studies have observed roles for sleep
and wake states in the efficacy of different forms of plasticity, but the results lack any explanation for how
state-specific plasticity selection may be occurring. Our lab has developed a robust way to study this
fundamental question by continuously collecting behavioral data and tracking single units from the visual cortex
(V1) of freely behaving rats during the well-established monocular deprivation (MD) paradigm. MD causes a
strong suppression of V1 firing via Hebbian LTD-like mechanisms over the first two days (MD1-2), which
induce homeostatic mechanisms that bring firing rates back to baseline levels over the next two days (MD3-4)
despite continued MD. Using this paradigm, we have already shown that this rebound, termed firing rate
homeostasis (FRH), occurs exclusively during active wake (AW; Hengen et al., 2016). Here, I will investigate
how AW specifically enables upward FRH. The major differences in V1 between AW (when upward FRH is
enabled) and both sleep and quiet wake (QW) states (when it is suppressed), are levels of cholinergic (ACh)
and noradrenergic (NE) input. ACh and NE contribute strongly to AW specific cortical activity patterns, are key
regulators of multiple forms of learning, and are known to cause a variety of modulatory effects in V1, allowing
for broad changes in synaptic efficacy. Further, my preliminary data confirms that inhibition of ACh neurons in
the basal forebrain (BF), which are the main source of ACh to neocortex, makes V1 LFP activity during AW
more like slow-wave-sleep. Therefore, I will test the hypothesis that upward FRH in V1 is gated by AW-
specific neuromodulatory inputs. I will test the role of BF ACh and LC NE neurons in enabling upward FRH
during AW using both chronic, global manipulations (DREADDs) and acute, local manipulations (optogenetic
approaches). Regardless of the outcome, these experiments will provide important insight into how behavioral
states can selectively coordinate distinct plasticity mechanisms in vivo and inform future hypotheses regarding
molecular targets and mechanisms of action for state-specific control of plasticity.
