Erika Correll

Prepulse inhibition (PPI) of the acoustic startle reflex is a widely used operational measure of sensorimotor gating that is disrupted in several neuropsychiatric disorders. PPI deficits are a hallmark feature of schizophrenia, often associated with attentional and cognitive impairments. Although PPI is extensively used in translational and preclinical research, the cellular and circuit mechanisms underlying this phenomenon remain incompletely understood, even under physiological conditions. Recent evidence suggests that noncholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the caudal pontine reticular nucleus (PnC) contribute to PPI. Here, we investigated the role of PPTg glutamatergic neurons in acoustic startle and PPI. Tract tracing, immunohistochemical analyses, and in vitro whole-cell recordings in wild-type male and female mice demonstrated that PPTg glutamatergic neurons innervate the PnC and establish excitatory synapses onto PnC neurons. Optogenetic inhibition of PPTg→PnC glutamatergic synapses in vivo increased PPI across interstimulus intervals (ISIs) without altering baseline startle responses. In contrast, optogenetic activation of this pathway did not modify PPI. However, activation of PPTg–PnC glutamatergic projections instead of an acoustic prepulse bidirectionally modulated startle responses in a time-dependent manner, suppressing startle at short ISIs while enhancing startle at longer intervals. Additionally, while 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 also activate PnC glutamatergic giant neurons. Together, our findings identify a novel temporally dependent excitatory mechanism within the brainstem startle circuit, through which PPTg glutamatergic neurons modulate sensorimotor gating.

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 Statement: The 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.

Traumatic brain injury (TBI) affects over 69 million people annually worldwide, and those with pre-existing depression have worse recovery. The molecular mechanisms that may contribute to poor recovery after TBI with co-morbid depression have not been established. TBI and depression have many commonalities including volume changes, myelin disruption, changes in proliferation, and changes in glutamatergic signaling. We used a well-established animal model of depression, the Wistar Kyoto (WKY) rat, to elucidate changes after TBI that may influence the recovery trajectory. We compared the histological and molecular outcomes in the hippocampal dentate gyrus after experimental TBI using the lateral fluid percussion injury (LFPI) in the WKY and the parent Wistar (WIS) strain. We showed that WKY had exaggerated myelin loss after LFPI and baseline deficits in proliferation. In addition, we showed that while after LFPI WIS rats exhibited glutamate receptor subunit changes, namely increased GluN2B, the WKY rats failed to show such injury-related changes. These differential responses to LFPI helped to elucidate the molecular characteristics that influence poor recovery after TBI in those with pre-existing depression and may lead to targets for future therapeutic interventions.