Biology subjects

Fenelon, K.

Publications and source records attributed to Fenelon, K..

5 recordsLinked to original sources

bioRxiv2025

Targeting Amygdala-Brainstem Synapses to Reverse Prepulse Inhibition Deficits

Sensorimotor gating, a fundamental pre-attentive process, can be assessed using the acoustic prepulse inhibition (PPI) assay. PPI deficits are a hallmark endophenotype of schizophrenia and are observed across various neuropsychiatric disorders, often predicting symptoms such as attention impairments, psychosis, and other cognitive/motor dysfunctions. Reversal of PPI deficits is routinely tested in disease models as a preclinical trial for antipsychotic drug screening. However, the cellular and circuit-level mechanisms underlying PPI deficits remain unclear, limiting therapeutic progress. We recently identified an uncharted pathway in mice, by which glutamatergic neurons in the central nucleus of the amygdala (CeA) activate glycinergic neurons in the caudal pontine reticular nucleus (PnC), contributing to PPI regulation. Given the prevalence of amygdala dys-function in disorders associated with PPI deficits, CeA-PnC glutamatergic synapses represent a novel therapeutic target. Here, using "Cal-Light," an in vivo Ca2+-dependent photo-tagging approach, we precisely identified CeA and PnC neurons active during acoustic startle and PPI with high spatiotemporal resolution. Furthermore, we used mice carrying homozygous deficiency in PRODH, a schizophrenia-relevant gene encoding proline dehydrogenase and modulating PPI. While Prodh-/- mice showed aberrant CeA neuronal properties and reduced PPI levels, we restored PPI by photo-activating CeA-PnC glutamatergic synapses, underscoring their involvement in pathological states. These findings provide new mechanistic insights into the amygdala-brainstem circuitry that underlies PPI deficits, offering new potential for therapeutic interventions.

neuroscience↗

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↗

bioRxiv2023

Deciphering the role of brainstem glycinergic neurons during startle and prepulse inhibition

Prepulse inhibition (PPI) of the auditory startle response is the gold standard operational measure of sensorimotor gating. Affected by various neurological and neuropsychiatric illnesses, PPI also declines during aging. While PPI deficits are often associated with cognitive overload, attention impairments and motor dysfunctions, their reversal is routinely used in experimental systems for drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. Recent evidence shows that neurons located in the brainstem caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2+) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI via an uncharted pathway. Using tract-tracing and immunohistochemical analyses in GlyT2-eGFP mice, we reveal the neuroanatomical location of CeA glutamatergic neurons innervating GlyT2+ neurons. Our precise in vitro optogenetic manipulations coupled to field electrophysiological recordings demonstrate that CeA glutamatergic inputs do suppress auditory neurotransmission in PnC neurons but not via action on transmitter release from auditory afferents. Rather, our data is consistent with excitatory drive onto GlyT2+ neurons. Indeed, our PPI experiments in vivo demonstrate that optogenetic activation of GlyT2+ PnC neurons increases PPI and is sufficient to induce PPI, clarifying the crucial role of these neurons in young GlyT2-Cre mice. In contrast, in older GlyT2-Cre mice, PPI is reduced and not further altered by optogenetic inhibition of GlyT2+ neurons. We conclude that GlyT2+ PnC neurons innervated by CeA glutamatergic inputs are crucial for PPI and we highlight their reduced activity during the age-dependent decline in PPI. SIGNIFICANCE STATEMENTSensorimotor gating is a pre-attentive mechanism that declines with age and that is affected by neuropsychiatric and neurological disorders. Prepulse inhibition (PPI) of startle commonly measures sensorimotor gating to assess cognitive and motor symptoms and to screen drug efficacy. Yet, the neuronal mechanisms underlying PPI are still unresolved, limiting therapeutic advances. Here, we identify brainstem glycinergic neurons essential for PPI using tract tracing, in vitro electrophysiology and precise in vivo optogenetic manipulations during startle measurements in mice. Innervated by amygdala glutamatergic inputs, we show that these glycinergic neurons are essential and sufficient to induce PPI in young mice. In contrast, these neurons do not contribute to PPI in older mice. We provide new insights to the theoretical construct of PPI.

neuroscience↗

bioRxiv2022

Cell-specific occupancy dynamics between the pioneer-like factor Opa/ZIC and Ocelliles/OTX regulate early head development in embryos

During development, embryonic patterning systems direct a set of initially uncommitted pluripotent cells to differentiate into a variety of cell types and tissues. A core network of transcription factors, such as Zelda/POU5F1, Odd-paired (Opa)/ZIC and Ocelliless (Oc)/OTX, are conserved across animals. While Opa is essential for a second wave of zygotic activation after Zelda, it is unclear whether Opa drives head cell specification past gastrulation onset, in the Drosophila embryo. Our hypothesis is that Opa and Oc are interacting with distinct cis-regulatory regions for shaping cell fates in the embryonic head. Using super-resolution microscopy and epigenomic meta-analysis of single cell RNAseq datasets we find that opas and ocs overlapping expression domains are dynamic in the head region, with both factors being simultaneously transcribed at the blastula stage. However, analysis of single-embryo RNAseq data reveals a subgroup of Opa-bound genes to be Opa-independent in the cellularized embryo. Interrogation of these genes against Oc ChIPseq combined with in situ data, suggests that Opa is competing with Oc for the regulation of a subgroup of genes later in gastrulation. Specifically, we find that Oc binds to late, head-specific enhancers independently and activates them in a head-specific wave of zygotic transcription, suggesting distinct roles for Oc in the blastula and gastrula stages.

developmental biology↗

bioRxiv2021

Shedding light on the contribution of amygdalar excitatory projections to prepulse inhibition of the auditory startle reflex

BackgroundSensorimotor gating is a fundamental neural filtering process that allows attention to be focused on a given stimulus. Sensory gating, commonly measured using the prepulse inhibition (PPI) of the auditory startle reflex task, is impaired in patients suffering from various neurological and psychiatric disorders, including schizophrenia. Because PPI deficits are often associated with attention and cognitive impairments, they are widely used as biomarkers in pre-clinical research for anti-psychotic drug screening. Yet, the neurotransmitter systems and synaptic mechanisms underlying PPI are still not resolved, even under physiological conditions. Recent evidence ruled out the longstanding hypothesis that PPI is mediated by midbrain cholinergic inputs to the caudal pontine reticular nucleus (PnC). Instead, glutamatergic, glycinergic and GABAergic inhibitory mechanisms are now suggested to be crucial for PPI, at the PnC level. Since amygdalar dysfunctions affect PPI and are common to pathologies displaying sensorimotor gating deficits, the present study was designed to test that direct projections to the PnC originating from the amygdala, contribute to PPI. ResultsUsing Wild Type and transgenic mice expressing eGFP under the control of the glycine transporter type 2 promoter (GlyT2-eGFP mice), we first employed tract-tracing, morphological reconstructions and immunohistochemical analyses to demonstrate that the central nucleus of the amygdala (CeA) sends glutamatergic inputs latero-ventrally to PnC neurons, including GlyT2+ cells. Then, we showed the contribution of the CeA-PnC excitatory synapses to PPI in vivo by demonstrating that optogenetic inhibition of this connection decreases PPI, and optogenetic activation induces partial PPI. Finally, in GlyT2-Cre mice, whole-cell recordings of GlyT2+ PnC neurons in vitro paired with optogenetic stimulation of CeA fibers, as well as photo-inhibition of GlyT2+ PnC neurons in vivo, allowed us to implicate GlyT2+ neurons in the PPI pathway. ConclusionsOur results uncover a feed-forward inhibitory mechanism within the brainstem startle circuit by which amygdalar glutamatergic inputs and GlyT2+ PnC neurons play a key role in meditating PPI. We are providing new insights to the clinically-relevant theoretical construct of PPI, which is disrupted in various neuropsychiatric and neurodevelopmental diseases.

neuroscience↗