Amblyopia is the most common form of monocular vision loss and is induced by monocular impairment during a developmental critical period when conditions in the primary visual cortex (V1) are highly permissive towards experience-dependent synaptic plasticity. As the brain becomes less plastic with age, amblyopia becomes increasingly difficult to treat. A better understanding of how synaptic plasticity is regulated in V1 is thought to be necessary to develop better treatments for adult amblyopia. The induction and recovery from amblyopia are both due to changes in the strength of excitatory synapses onto cortical pyramidal neurons (PYRs), which increase or decrease depending on the correlation of activity in pre-and post- synaptic neurons. The probability of correlation, and therefore plasticity, is influenced by inhibitory circuits that control PYR excitability. In V1, two inhibitory circuits modulate ocular dominance plasticity of PYRs. Parvalbumin-expressing interneurons (PVs) control PYR spiking output via somatic inhibition. Reduction of PV activity reactivates ocular dominance plasticity in adult V1. A second circuit is composed of interneurons that express either vasoactive intestinal peptide (VIPs), or somatostatin (SOMs), which together gate input onto the apical dendrite: when SOMS are inhibited by VIPs, cortico-cortical inputs onto the PYRs more strongly drive spiking output, reactivating ocular dominance plasticity. A better understanding of the how PV and the VIP/SOM circuits interact in the visual system will provide insight into cortical circuit function in other systems. Interestingly, both circuits can be manipulated non-invasively via dark exposure or voluntary locomotion, respectively. Both circuits represent attractive therapeutic targets for enhancing plasticity to treat adult amblyopia, but suffer from drawbacks. However, manipulating these two pathway simultaneously may synergistically promote ocular dominance plasticity. The interactions between these two inhibitory systems has not been thoroughly investigated. Therefore, I propose a series of 3 specific aims to determine how the two inhibitory systems interact to influence ocular dominance plasticity, and evaluate a combined therapeutic approach. First, in Aim 1, I will the hypothesis that enhanced PV-mediated somatic inhibition can override the enhancement of ocular dominance plasticity induced by voluntary locomotion: These experiments will employ PV-cre dependent expression of Gs-DREADD to enhance activity of PVs in mice locomoting on an air-suspending foam ball treadmill to promote ocular dominance plasticity.
In AIM 2, I will test the hypothesis that enhanced SOM excitability does not override the enhancement of ocular dominance plasticity induced by dark exposure: These experiments will employ SOM-cre dependent expression of Gs-DREADD to enhance the activity of SOMs and suppress intracortical inputs onto PYRs while simultaneously using dark exposure to suppress PVs and reactivate ocular dominance plasticity. Lastly, in AIM 3, I will test the hypothesis that simultaneous reduction of PV and SOM excitability will act synergistically to maximally enhance ocular dominance plasticity in the adult visual cortex: These experiments will combine dark exposure and voluntary locomotion to non- invasively recruit the PV and VIP/SOM circuits and powerfully enhance recovery of visual acuity in amblyopic mice.
Amblyopia, the most common form of monocular vision loss, is treatable in adolescents but resistant to treatment in adults due to the loss of synaptic plasticity in the visual cortex with age. Recent work in rodents has demonstrated two independent inhibitory circuits that can be non-invasively manipulated to enhance synaptic plasticity in the visual cortex via dark exposure or voluntary locomotion. While each of these is a potential avenue for amblyopia therapy, little is known about how these two circuits interact or if their effects can be combined synergistically to maximally enhance plasticity, a hypothesis I specifically test in this proposal that would hold great promise for the treatment of adult amblyopes.
| Bridi, Michelle C D; de Pasquale, Roberto; Lantz, Crystal L et al. (2018) Two distinct mechanisms for experience-dependent homeostasis. Nat Neurosci 21:843-850 |
