Biology subjects

Martinetti, L. E.

Publications and source records attributed to Martinetti, L. E..

4 recordsLinked to original sources

bioRxiv2025

Midbrain Glutamatergic Neurons Modulate the Acoustic Startle Reflex and Prepulse Inhibition in Mice

Prepulse inhibition (PPI) of the auditory startle reflex task is a widely recognized operational measure of sensorimotor gating. PPI deficits are a hallmark feature of schizophrenia, often associated with attentional and cognitive impairments. Despite its extensive use in preclinical research for screening antipsychotic drugs, the precise cellular and circuit mechanisms underlying PPI remain unclear, even under physiological conditions. Recent evidence suggests that non-cholinergic inputs from the pedunculopontine tegmental nucleus (PPTg) to the caudal pontine reticular nucleus (PnC) mediate PPI. In this study, we investigated the contribution of PPTg glutamatergic neurons to acoustic startle and PPI. Tract-tracing, immuno-histochemical analyses, and in vitro whole-cell recordings in wild-type mice confirmed that PPTg glutamatergic neurons innervate the PnC. Optogenetic inhibition of PPTg-PnC glutamatergic synapses in vivo resulted in increased PPI across various interstimulus intervals. Notably, while optogenetic activation of this pathway had no additional effect on startle and PPI, activation of this connection alone before startle stimulation reduced startle at short interstimulus intervals and increased startle at longer intervals. Furthermore, although PPTg glutamatergic inputs target PnC glycinergic neurons, our in vitro whole-cell recordings combined with optogenetic stimulation at PPTg-PnC synapses revealed that PPTg glutamatergic inputs activate PnC glutamatergic giant neurons. Our findings identify a feed-forward excitatory mechanism within the brainstem startle circuit, whereby PPTg glutamatergic inputs modulate PnC neuronal activity. These results provide new insights into the clinically relevant theoretical construct of PPI, which is disrupted in various neuropsychiatric and neurological disorders. Significance StatementThe pedunculopontine tegmental nucleus (PPTg) contributes to prepulse inhibition (PPI) of startle, a translational measure of sensorimotor gating that is impaired in neuropsychiatric disorders, including schizophrenia. While PPTg cholinergic neurons have been shown not to contribute to PPI, the mechanisms by which non-cholinergic PPTg neurons modulate PPI remain incompletely understood. Here, combining tract-tracing, optogenetics, in vitro electrophysiology, and in vivo startle testing in mice, we show that PPTg glutamatergic neurons that innervate startle-mediating neurons of the caudal pontine reticular nucleus (PnC) play a critical role in PPI. Their activation modulates startle responses in a time-dependent manner, either decreasing or increasing startle magnitude. These findings refine our understanding of sensorimotor gating neural mechanisms and may inform therapeutic strategies.

neuroscience↗

bioRxiv2024

Motor Control of Distinct Layer 6 Corticothalamic Feedback Circuits

Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extra-sensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in Dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) projecting CT neurons located in lower L6a than VPm-only projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements. SIGNIFICANCE STATEMENTLayer 6 corticothalamic (L6 CT) feedback circuits are ubiquitous across mammalian species and modalities, and their activities have a strong influence on thalamic excitability and information throughput to the neocortex. Despite clear evidence of CT effects on the thalamus, we know relatively little about how CT cells themselves are regulated. Our results show that input from the primary motor cortex strongly excites a subclass of CT neurons in the primary somatosensory cortex that innervate both core and higher-order somatosensory nuclei rather than those exclusively targeting core somatosensory thalamus. The cortico-cortico-thalamic pathway formed by these connections establishes a circuit-level substrate for supporting CT influence operating under the guidance of ongoing motor activities.

neuroscience↗

bioRxiv2021

Short-term dynamics of long-range corticocortical synapses revealed by selective optical stimulation

Short-term plasticity regulates the strength of central synapses as a function of previous activity. In the neocortex, direct synaptic interactions between areas play a central role in cognitive function, but the activity-dependent regulation of these long-range corticocortical connections and their impact on a postsynaptic target neuron is unclear. Here, we use an optogenetic strategy to study the connections between mouse primary somatosensory and motor cortex. We found that short-term facilitation was strong in both corticocortical synapses, resulting in far more sustained responses than local intra-cortical and thalamocortical connections. A major difference between pathways was that the synaptic strength and magnitude of facilitation were distinct for individual excitatory cells located across all cortical layers and specific subtypes of GABAergic neurons. Facilitation was dependent on the presynaptic calcium sensor synaptotagmin-7 and altered by several optogenetic approaches. Current-clamp recordings revealed that during repetitive activation, the short-term dynamics of corticocortical synapses enhanced the excitability of layer 2/3 pyramidal neurons, increasing the probability of spiking with activity. Furthermore, the properties of the connections linking primary with secondary somatosensory cortex resemble those between somatosensory-motor areas. These short-term changes in transmission properties suggest long-range corticocortical synapses are specialized for conveying information over relatively extended periods.

neuroscience↗

bioRxiv2020

A human TSC1 mutation screening platform in GABAergic cortical interneurons for Genotype to Phenotype assessments

Tuberous Sclerosis Complex is a complex syndrome that affects multiple organs and is caused by dysfunction of either the TSC1 or TSC2 genes. One of the least understood features of TSC is the impact of TSC1&2 variants on brain phenotypes, including elevated rates of autism spectrum disorder and seizures. Moreover, while a great deal of work has uncovered how loss of either gene can alter various neural cell types, the impact of many variants in TSC and on these cell types is poorly understood. In particular, missense variants that cause minor changes in the proteins are expected to cause functional changes that differ from a complete loss of the protein. Herein, we examined how some missense variants in TSC1 impacted the development of cortical inhibitory interneurons, a cell type whose molecular, cellular and physiological properties are known to be altered after loss of mouse Tsc1. Importantly, we found that most missense variants complemented phenotypes caused by loss of Tsc1 and resulting in elevated MTOR activity as well as several cell intrinsic physiological properties. However, distinct variants showed deficits in complementing an increase in parvalbumin levels, which is observed after loss of Tsc1 and demonstrated smaller amplitudes of after hyperpolarizations. These data suggest subtle but sensitive phenotypes can be detected by some TSC1 missense variants and provide an in vivo system in which to better assess TSC variants.

neuroscience↗