This in silico study predicts the impact that the single-cell neuronal morphological alterations will have on the striatal microcircuit connectivity. We find that the richness in the topological striatal motifs is significantly reduced in Parkinson's disease (PD), highlighting that just measuring the pairwise connectivity between neurons gives an incomplete description of network connectivity. Moreover, we predict how the resulting electrophysiological changes of striatal projection neuron excitability together with their reduced number of dendritic branches affect their response to the glutamatergic drive from the cortex and thalamus. We find that the effective glutamatergic drive is likely significantly increased in PD, in accordance with the hyperglutamatergic hypothesis.

Trial-by-trial variability is a ubiquitous property of neuronal activity in vivo which shapes the stimulus response. Computational models have revealed how local network structure and feedforward inputs shape the trial-by-trial variability. However, the role of input statistics and different interneuron subtypes in this process is less understood. To address this, we investigate the dynamics of stimulus response in a cortical microcircuit model with one excitatory and three inhibitory interneuron populations (PV, SST, VIP). Our findings demonstrate that the balance of inputs to different neuron populations and input covariances are the primary determinants of output trial-by-trial variability. The effect of input covariances is contingent on the input balances. In general, the network exhibits smaller output trial-by-trial variability in a PV-dominated regime than in an SST-dominated regime. Importantly, our work reveals mechanisms by which output trial-by-trial variability can be controlled in a context, state, and task-dependent manner.

Striatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behaviour, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinson’s disease (PD), both morphological and electrophysiological striatal neuronal features are altered. Our goal with this \textit{in-silico} study is twofold: a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single neuron level, and b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary we find that the richness of the connectivity motifs is significantly decreased during PD, while at the same time a substantial enhancement of the effective glutamatergic drive to striatum is present.