Biology subjects

Henderson, F.

Publications and source records attributed to Henderson, F..

6 recordsLinked to original sources

bioRxiv2026

Dlx5/6 regulate perineuronal net-synapse coupling and stabilize adult cortical Parvalbumin neurons networks

The transcriptional mechanisms that maintain adult Parvalbumin (PV) interneuron function and cortical network stability remain poorly understood. We previously showed that the inactivation in GABAergic neurons of Dlx5/6, coding for transcription factors, disrupts social interaction and reduces PV interneuron density in the prefrontal cortex. Here, combining transcriptional and histological analyses with ex vivo electrophysiological and in vivo electroencephalographical (EEG) recordings, we show that Dlx5/6 regulate a molecular program controlling perineuronal net (PNN) homeostasis in the adult cortex. Dlx5/6 inactivation dysregulated the expression of multiple PNN-associated genes and induced region-specific remodelling of PNN mesh architecture in the prefrontal and somatosensory cortices. These structural changes were accompanied by alterations in excitatory and inhibitory synaptic organization and by a disrupted coupling between local PNN structure and synaptic properties. Ex vivo electrophysiological recordings revealed that fast-spiking interneurons displayed altered intrinsic properties and reduced excitatory synaptic drive in a region-specific manner, while EEG recordings during social interaction showed impaired recruitment of prefrontal gamma oscillations. Together, these findings identify Dlx5/6 as regulators of adult PV interneuron stability, linking extracellular matrix homeostasis to synaptic organization and cortical network dynamics. More broadly, it provides a new mechanistic framework connecting Dlx5/6 function to PV-related pathological phenotypes, including neuropsychiatric disorders. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/740286v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@147c75dorg.highwire.dtl.DTLVardef@171e7d9org.highwire.dtl.DTLVardef@12c5c67org.highwire.dtl.DTLVardef@166790d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses

Mood and anxiety disorders display robust sex differences in prevalence, symptom profile, and treatment outcomes, yet the circuit mechanisms underlying this sex bias remain unclear. Here, we identify a serotonergic (5-HT) pathway from the median raphe region (MRR) to the ventral hippocampus (vHP) that drives sex-specific anxiety regulation in mice. Using a multimodal approach combining electrophysiology, fiber photometry, and optogenetics, we show that vHP-projecting 5-HT neurons (5-HTvHP) in the MRR are intrinsically hyperexcitable in females and exhibit delayed adaptation during exposure to aversive environments. At baseline, female mice displayed greater avoidance and reduced risk-assessment behavior. Optogenetic activation of this pathway selectively enhanced anxiety-like behavior and stress-related grooming in females, while leaving locomotion unaffected. Fiber photometry revealed that grooming episodes coincide with transient suppression of 5-HTvHP activity, suggesting an adaptive feedback mechanism to downregulate serotonergic tone under elevated anxiety. Moreover, activation of this pathway disrupted hippocampal theta dynamics during habituation to a novel arena exclusively in females, revealing serotonergic modulation of anxiety and novelty processing. These results were consistent with the identification of sex-specific M-currents, which constrained excitability in male MRR 5-HTvHP neurons, while being largely absent in females. Collectively, our findings uncover a hyperexcitable MRR-vHP serotonergic circuit that drives female-specific anxiety states, providing a mechanistic framework for understanding sex-specific vulnerability to mood and anxiety disorders.

neuroscience↗

bioRxiv2022

Parallel streams of raphe VGLUT3-positive inputs target the dorsal and ventral hippocampus in each hemisphere.

The hippocampus (HP) receives neurochemically diverse inputs from the raphe nuclei, including glutamatergic fibers characterized by the expression of the vesicular glutamate transporter VGLUT3. These raphe-HP VGLUT3 (VGLUT3HP) projections have been suggested to play a critical role in HP functions, yet a complete anatomical overview of raphe VGLUT3 projections to the forebrain, and in particular the HP, is lacking. Using anterograde viral tracing, we describe largely non-overlapping VGLUT3-positive projections from the dorsal raphe (DR) and median raphe (MnR) to the forebrain, with the HP receiving inputs from the MnR. A limited subset of forebrain regions such as the amygdaloid complex, claustrum and hypothalamus receive projections from both the DR and MnR that remain largely segregated. This highly complementary anatomical pattern suggests contrasting roles for DR and MnR VGLUT3 neurons. To further analyse the topography of VGLUT3 raphe projections to the HP, we used retrograde tracing and found that VGLUT3HP neurons distribute over several raphe sub-regions (including the MnR, paramedian raphe and B9 nucleus) and lack co-expression of serotonergic markers. Strikingly, two-color retrograde tracing unraveled two parallel streams of VGLUT3-positive projections targeting the dorsal and ventral poles of the HP. These results demonstrate highly organized and segregated VGLUT3-positive projections to the HP, suggesting independent modulation of HP functions such as spatial memory and emotion-related behavior.

neuroscience↗

bioRxiv2022

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep.

The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNF controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNF comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNF attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNF that acts at the neuronal circuitry through dynamic control of phosphorylation.

neuroscience↗

bioRxiv2022

Microglial TNFα controls GABAAR plasticity, slow waves and memory consolidation during sleep

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNF. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNF and P2RX7. We further show that microglia-specific depletion of TNF alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves and support memory consolidation.

neuroscience↗

bioRxiv2020

Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer's Disease Brains

Tau aggregates are present in a large number of neurodegenerative diseases known as "tauopathies", including Alzheimers disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus. Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for "prion-like" tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.

pathology↗