Intrinsic Neural Timescales in the Temporal Lobe Support an Auditory Processing Hierarchy.

During rest, intrinsic neural dynamics manifest at multiple timescales, which progressively increase along visual and somatosensory hierarchies. Theoretically, intrinsic timescales are thought to facilitate processing of external stimuli at multiple stages. However, direct links between timescales at rest and sensory processing, as well as translation to the auditory system are lacking. Here, we measured intracranial EEG in 11 human patients with epilepsy (4 women), while listening to pure tones. We show that, in the auditory network, intrinsic neural timescales progressively increase, while the spectral exponent flattens, from temporal to entorhinal cortex, hippocampus, and amygdala. Within the neocortex, intrinsic timescales exhibit spatial gradients that follow the temporal lobe anatomy. Crucially, intrinsic timescales at baseline can explain the latency of auditory responses: as intrinsic timescales increase, so do the single-electrode response onset and peak latencies. Our results suggest that the human auditory network exhibits a repertoire of intrinsic neural dynamics, which manifest in cortical gradients with millimeter resolution and may provide a variety of temporal windows to support auditory processing.SIGNIFICANCE STATEMENT Endogenous neural dynamics are often characterized by their intrinsic timescales. These are thought to facilitate processing of external stimuli. However, a direct link between intrinsic timing at rest and sensory processing is missing. Here, with intracranial EEG, we show that intrinsic timescales progressively increase from temporal to entorhinal cortex, hippocampus, and amygdala. Intrinsic timescales at baseline can explain the variability in the timing of intracranial EEG responses to sounds: cortical electrodes with fast timescales also show fast- and short-lasting responses to auditory stimuli, which progressively increase in the hippocampus and amygdala. Our results suggest that a hierarchy of neural dynamics in the temporal lobe manifests across cortical and limbic structures and can explain the temporal richness of auditory responses.

Dopamine depletion induces neuron-specific alterations of GABAergic transmission in the mouse striatum.

Lack of dopamine (DA) in the striatum and the consequential dysregulation of thalamocortical circuits are major causes of motor impairments in Parkinson's disease. The striatum receives multiple cortical and subcortical afferents. Its role in movement control and motor skills learning is regulated by DA from the nigrostriatal pathway. In Parkinson's disease, DA loss affects striatal network activity and induces a functional imbalance of its output pathways, impairing thalamocortical function. Striatal projection neurons are GABAergic and form two functionally antagonistic pathways: the direct pathway, originating from DA receptor type 1-expressing medium spiny neurons (D1 R-MSN), and the indirect pathway, from D2 R-MSN. Here, we investigated whether DA depletion in mouse striatum also affects GABAergic function. We recorded GABAergic miniature IPSCs (mIPSC) and tonic inhibition from D1 R- and D2 R-MSN and used immunohistochemical labeling to study GABAA R function and subcellular distribution in DA-depleted and control mice. We observed slower decay kinetics and increased tonic inhibition in D1 R-MSN, while D2 R-MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABAA R subunits α1 or α2 were not affected, but there was a strong decrease in non-synaptic GABAA Rs containing these subunits, suggesting altered receptor trafficking. To broaden these findings, we also investigated GABAA Rs in GABAergic and cholinergic interneurons and found cell type-specific alterations in receptor distribution, likely reflecting changes in connectivity. Our results reveal that chronic DA depletion alters striatal GABAergic transmission, thereby affecting cellular and circuit activity. These alterations either result from pathological changes or represent a compensatory mechanism to counteract imbalance of output pathways.

Cell type-specific distribution of GABAA receptor subtypes in the mouse dorsal striatum.

The striatum is the main input nucleus of the basal ganglia, mediating motor and cognitive functions. Striatal projection neurons are GABAergic medium spiny neurons (MSN), expressing either the dopamine receptor type 1 (D1 -R MSN) and forming the direct, movement-promoting pathway, or dopamine receptor type 2 (D2 -R MSN), forming the indirect movement-suppressing pathway. Locally, activity and synchronization of MSN are modulated by several subtypes of GABAergic and cholinergic interneurons. Overall, GABAergic circuits in the striatum remain poorly characterized, and little is known about the intrastriatal connectivity of interneurons and the distribution of GABAA receptor (GABAA R) subtypes, distinguished by their subunit composition, in striatal synapses. Here, by using immunofluorescence in mouse tissue, we investigated the distribution of GABAA Rs containing the α1 , α2 , or α3 subunit in perisomatic synapses of striatal MSN and interneurons, as well as the innervation pattern of D1 R- and D2 R-MSN soma and axonal initial segment (AIS) by GABAergic and cholinergic interneurons. Our results show that perisomatic GABAergic synapses of D1 R- and D2 R-MSN contain the GABAA R α1 and/or α2 subunits, but not the α3 subunit; D2 R-MSN have significantly more α1 -GABAA Rs on their soma than D1 R-MSN. Further, interneurons have few perisomatic synapses containing α2 -GABAA Rs, whereas α3 -GABAA Rs (along with the α1 -GABAA Rs) are abundant in perisomatic synapses of CCK+ , NPY+ /SOM+ , and vAChT+ interneurons. Each MSN and interneuron population analyzed received a distinct pattern of GABAergic and cholinergic innervation, complementing this postsynaptic heterogeneity. In conclusion, intra-striatal GABAergic circuits are distinguished by cell-type specific innervation patterns, differential expression and postsynaptic targeting of GABAA R subtypes.