Disinhibitory circuit motifs in the mouse primary somatosensory (barrel) cortex
by Felix Preuß
Date of Examination:2024-02-26
Date of issue:2025-02-24
Advisor:Prof. Dr. Jochen F. Staiger
Referee:Prof. Dr. Swen Hülsmann
Referee:Prof. Dr. Tobias Moser
Persistent Address:
http://dx.doi.org/10.53846/goediss-11110
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Abstract
English
The barrel cortex is the part of the rodent neocortex where the tactile information from the whiskers is processed. In the barrel cortex, each whisker is represented by a single cortical column isomorphic to the whiskers on the snout. Since the cortical column is considered to be the basic unit of all computations, the barrel cortex became a fruitful model for the study of columnar microcircuits in the mammalian neocortex. The majority of cortical neurons are excitatory (≈85%) and release the neurotransmitter glutamate while only roughly 15% are inhibitory and release γ-amino butyric acid (GABA). These cell types are intricately integrated into the local microcircuit to maintain the balance between excitation and inhibition. The somatostatin- (SST) expressing cells are one subpopulation of GABAergic interneurons (IN) that are effectively controlling excitatory cells. They are targeted by other GABAergic IN, namely parvalbumin- (PV) and vasoactive intestinal polypeptide- (VIP) expressing cells, forming a circuit motif, which is known as disinhibition. By targeting SST cells, PV and VIP cells are able to reduce the inhibitory drive on excitatory cells. Although disinhibitory circuits are extensively studied in modern neuroscience, little is known about the disinhibitory circuitry of L5 SST cells in mouse barrel cortex. L5 is, according to the canonical microcircuit, the main output layer of the barrel cortex. Furthermore, it is unknown whether individual presynaptic PV or VIP cells are able to modulate the output of postsynaptic SST cells. My aim is to extend our knowledge of the disinhibitory circuitry of SST cells and to analyse the functionality of the PV to SST and the VIP to SST circuit motifs. Therefore, this study is divided into two chapters. In the first chapter, three novel disinhibitory circuits in mouse barrel cortex targeting L5 SST cells are described. Intralaminar whole cell patch clamp recordings revealed that both PV and VIP cells reliably target L5 SST cells (connectivity rates: ≈25% for PV to SST; ≈23% for VIP to SST). Translaminar recordings demonstrated that also L2/3 VIP cells are connected to L5 SST cells with a similar connection probability as the intralaminar connection (≈30%). However, L2/3 PV cells were not frequently connected to L5 SST cell as only one out of 48 analysed pairs (≈2.1%) showed a connection. PV and VIP connections displayed cell type- specific differences in unitary synaptic properties and short-term synaptic plasticity. PV connections were larger in amplitude and shorter in latency. Moreover, PV connections were depressing at all tested frequencies (1, 8, and 40 Hz) whereas VIP connections were facilitating but only at high-frequency stimulation (40 Hz). In addition, we found reciprocally connected pairs in all three analysed connections. This opens a window of opportunity for SST cells to also inhibit their own inhibitors, adding another level of complexity to the dis/inhibitory circuitry in mouse barrel cortex. In the second chapter, we analysed the functionality of the PV to SST and VIP to SST cell circuits in L2/3 of mouse barrel cortex. While inducing action potential firing in postsynaptic SST cells, we analysed the effect of simultaneous presynaptic PV and VIP cell supratreshold stimulation. The known or hypothesized differences in unitary synaptic properties and subcellular distribution of synapses let us assume differences in action potential modulation by PV or VIP cells on postsynaptic SST target cells. However, stimulation of individual PV and of individual VIP cells was able to significantly reduce action potential firing in postsynaptic SST cells. Within both connections, we saw a large variety of effect strengths. When comparing effect strength of PV to SST and VIP to SST cell connections there was no significant difference in spike loss or inter-spike interval increase. When normalizing effect strength for the number of presynaptic action potentials, the VIP effect was significantly stronger than of PV cells. A short stimulation of PV and VIP cells, when appropriately timed, was able to significantly delay firing of postsynaptic SST cells. However, again there was no significant difference in effect strength between PV to SST and VIP to SST cell connections. Morphological reconstructions and subsequent putative contact site analysis did not reveal significant differences between both groups. In line with other observations, putative contact site location did not correlate with spike loss in reconstructed pairs. Our findings question the concept of input versus output control by specific inhibitory cell types. In summary, we discovered novel intralaminar disinhibitory circuit motifs of L5 SST, homologous to their supragranular counterparts. By investigating translaminar circuit motifs, we found a VIP cell-specific circuit from L2/3 to L5 SST cells, which displayed similar unitary synaptic properties and short-term plasticity as the intralaminar L5 to L5 circuit. Furthermore, we were able to show that, against current concepts, activation of individual PV and VIP cells was able to decrease the output of postsynaptic SST cells.
Keywords: Barrel Cortex; GABAergic Interneurons; Circuit Motifs; Somatostatin; Vasoactive Intestinal Polypeptide; Parvalbumin
