Impact of neuromodulators on the maturation and rewiring of neural circuitry for vestibular-dependent behaviors

Abstract

Experience-dependent plasticity during early postnatal development of the nervous system enables hardwiring of neural circuits to sensory experiences. Disruptions in neurodevelopment within this time window result in deficits that persist into adulthood. γ-aminobutyric acid (GABA) and endocannabinoid (eCB) are crucial for the control of postnatal synaptic plasticity. Findings from our laboratory revealed that neonatal blockade of GABAergic transmission in the brainstem vestibular nucleus (VN) of rats led to an over-activation of neurons in the anterodorsal thalamic nucleus (ADN), a key station in the ascending vestibular pathway for spatial cognition. This was accompanied by deficits in spatial navigation observed in adulthood. Similar behavioural deficits were also observed with over-activation of eCB receptors in VN at the neonatal stage.

In this study, we aimed at rescuing behavioural deficits by reinstating experience-dependent plasticity in adult rats that had received neonatal perturbation of either GABA or eCB receptors in the VN. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is well known to re-activate neuroplasticity in several sensory systems of adult animals. We hypothesized that concurrent treatment of FLX with counter-clockwise wobble rotation (WOB) in adult rats can reinstate the plasticity of early-deranged vestibular circuitries and provide the necessary vestibular-specific sensory input to reshape the vestibular circuitry for executing normal spatial navigation.

To demonstrate experience-dependent rewiring in the vestibular circuit during this period of plasticity, we examined the level of activation among vestibular-related neurons in the ADN. Combined treatment of FLX+WOB in rats with neonatal vestibular derangement restored vestibular-related activity in the ADN, as indicated by the number of functionally activated Fos-immunoreactive neurons. In addition, rats that suffered from neonatal vestibular derangement showed a recovery in spatial navigation ability. Nevertheless, sole treatment of FLX or WOB alone did not result in such recovery at both the cellular and behavioural level.

Given that enhanced VN activity to the thalamus led to derangement of spatial navigation, we probed the possible role of inhibitory VN neurons in spatial navigation. With the use of chemogenetic tools, we modulated the activity of two major types of inhibitory interneurons in the VN, i.e. parvalbumin (PV+) and somatostatin (SST+) interneurons. We found that these interneurons did not play a significant role in spatial navigation, though there were indications that these interneurons were indeed involved in vestibulospinal reflexes for maintenance of posture and balance.

Altogether, we demonstrate the possibility of engaging neuromodulators in reshaping deranged neural circuitries in the adult VN by experience-dependent rewiring during a period of FLX-induced plasticity. This forms the basis for the design and refinement of therapeutic strategies for neurorehabilitation. In addition, the results provide insights towards the role of inhibitory interneurons in the central vestibular system.