Activation of parvalbumin-expressing neurons reconfigures neuronal ensembles in murine striatal microcircuits.

The striatum is the largest entrance to the basal ganglia. Diverse neuron classes make up striatal microcircuit activity, consisting in the sequential activation of neuronal ensembles. How different neuron classes participate in generating ensemble sequences is unknown. In control mus musculus brain slices in vitro, providing excitatory drive generates ensemble sequences. In Parkinsonian microcircuits captured by a highly recurrent ensemble, a cortical stimulus causes a transitory reconfiguration of neuronal groups alleviating Parkinsonism. Alternation between neuronal ensembles needs interconnectivity, in part due to interneurons, preferentially innervated by incoming afferents. One main class of interneuron expresses parvalbumin (PV+ neurons) and mediates feed-forward inhibition. However, its more global actions within the microcircuit are unknown. Using calcium imaging in ex vivo brain slices simultaneously recording dozens of neurons, we aimed to observe the actions of PV+ neurons within the striatal microcircuit. PV+ neurons in active microcircuits are 5%-11% of the active neurons even if, anatomically, they are <1% of the total neuronal population. In resting microcircuits, optogenetic activation of PV+ neurons turns on circuit activity by activating or disinhibiting, more neurons than those actually inhibited, showing that feed-forward inhibition is not their only function. Optostimulation of PV+ neurons in active microcircuits inhibits and activates different neuron sets, resulting in the reconfiguration of neuronal ensembles by changing their functional connections and ensemble membership, showing that neurons may belong to different ensembles at different situations. Our results show that PV+ neurons participate in the mechanisms that generate alternation of neuronal ensembles, therefore provoking ensemble sequences.

Comparison of Actions between L-DOPA and Different Dopamine Agonists in Striatal DA-Depleted Microcircuits In Vitro: Pre-Clinical Insights.

Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.