Biology subjects

Kenney, J.

Publications and source records attributed to Kenney, J..

4 recordsLinked to original sources

bioRxiv2026

Psilocybin collapses visual change detection and drives cortical dynamics toward a state of surprise

Psilocybin profoundly alters visual perception, yet the neuronal mechanisms underlying these effects remain unclear. Here we combined large-scale Neuropixels recordings with cell-type specific optogenetics in head-fixed mice performing a visual change-detection task. Psilocybin severely impaired task performance without overt motor deficits. In cortex, the drug modestly suppressed activity of layer 5 neurons while preserving representations of image identity. By contrast, psilocybin imposed a 4-Hz oscillation on visually evoked activity that preferentially affected neurons encoding image change rather than image identity. Under psilocybin, expected image repetitions aberrantly recruited change-encoding ensembles and shifted cortical population dynamics towards trajectories normally evoked by genuine stimulus changes. These effects were strongest in somatostatin-expressing (SST) interneurons in visual cortex. The strength of this modulation depended on image structure and was greatest for images with clear, continuous contours, which preferentially recruited change-encoding ensembles. These findings demonstrate that psilocybin drives internally generated cortical surprise signals, providing a circuit mechanism for altered perception in the acute psychedelic state.

neuroscience↗

bioRxiv2024

A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish

Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) differentiation. However, little is known about the mechanisms directing Nr2f expression in ACs. Here, we identified a conserved enhancer 3 to the nr2f1a locus, which we call 3reg1-nr2f1a (3reg1), that can promote Nr2f1a expression in ACs. Sequence analysis of the enhancer identified putative Lef/Tcf and Foxf TF binding sites. Mutation of the Lef/Tcf sites within the 3reg1 reporter, knockdown of Tcf7l1a, and manipulation of canonical Wnt signaling support that Tcf7l1a is derepressed via Wnt signaling to activate the transgenic enhancer and promote AC differentiation. Similarly, mutation of the Foxf binding sites in the 3reg1 reporter, coupled with gain- and loss-of-function analysis supported that Foxf1 promotes expression of the enhancer and AC differentiation. Functionally, we find that Wnt signaling acts downstream of Foxf1 to promote expression of the 3reg1 reporter within ACs and, importantly, both Foxf1 and Wnt signaling require Nr2f1a to promote a surplus of differentiated ACs. CRISPR-mediated deletion of the endogenous 3reg1 abrogates the ability of Foxf1 and Wnt signaling to produce surplus ACs in zebrafish embryos. Together, our data support that downstream members of a conserved regulatory network involving Wnt signaling and Foxf1 function on a nr2f1a enhancer to promote AC differentiation in the zebrafish heart. Author SummaryVertebrate hearts are comprised of atrial chambers, which receive blood, and ventricular chambers which expel blood, whose functions need to be coordinated for proper blood circulation. During development, different genetic programs direct the development of these chambers within the vertebrate heart. Members of a family of genes called Nr2fs are conserved regulators of atrial chamber development in vertebrates, with mutations in Nr2f2 of humans being associated with congenital heart defects affecting the atrium. Here, we examine how the gene nr2f1a, which is required for normal atrial chamber development in the model zebrafish, is regulated. Using tools, including transgenic reporter lines and genetic mutants, we identify that factors previously shown to regulate atrial chamber development in mammals have conserved roles regulating a genetic element that promotes nr2f1a expression within developing atrial cells. Since there is a lack of understanding regarding regulation of Nr2f genes during vertebrate atrial cell development, our work provides insights into the conservation of genetic networks that promote heart development in vertebrates and if perturbed could underlie congenital heart defects.

developmental biology↗

bioRxiv2020

Mucosal immune stimulation with HSV-2 and polyICLC boosts control of viremia in SIVΔNef vaccinated rhesus macaques with breakthrough SIV infection

Development of an effective human immunodeficiency virus (HIV) vaccine is among the highest priorities in the biomedical research agenda. Adjuvants enhance vaccine efficacy, but in the case of HIV, strong or inappropriate immune activation may undermine protection by increasing HIV susceptibility. Co-infection with immunomodulatory pathogens may also impact vaccine efficacy. In the rhesus macaque rectal SIV{Delta}Nef live attenuated vaccine model, we utilized a low virulence HSV-2 infection and the double-stranded RNA viral mimic polyICLC as tools to probe the effects of distinct types of immune activation on HIV vaccine efficacy and explore novel correlates of protection from wild type SIV. Rectally administered HSV-2 and polyICLC impacted the protection conferred by mucosal SIV{Delta}Nef vaccination by favoring partial protection in animals with breakthrough infection following virulent SIV challenge ("Controllers"). However, SIV{Delta}Nef persistence in blood and tissues did not predict protection in this rectal immunization and challenge model. Non-controllers had similar SIV{Delta}Nef viremia as completely protected macaques, and while they tended to have less replication competent SIV{Delta}Nef in lymph nodes, controllers had no recoverable virus in the lymph nodes. Non-controllers differed from protected macaques immunologically by having a greater frequency of pro-inflammatory CXCR3+CCR6+ CD4 T cells in blood and a monofunctional IFN{gamma}-dominant CD8 T cell response in lymph nodes. Controller phenotype was associated with heightened IFN production during acute SIV infection and a greater frequency of CXCR5+ CD4 T cells in blood pre-challenge despite a lower frequency of cells with the T follicular helper (Tfh) cell phenotype in blood and lymph nodes. Our results establish novel correlates of immunological control of SIV infection while reinforcing the potential importance of T cell functionality and location in SIV{Delta}Nef efficacy. Moreover, this work highlights that triggering of mucosal immunity can aid mucosal vaccine strategies rather than undermine protection. AUTHOR SUMMARYAn efficacious HIV vaccine is essential to contain the HIV pandemic. Vaccine-mediated protection from HIV may be either enhanced or obstructed by mucosal immune activation; thus, the impact of adjuvants and underlying co-infections that lead to immune activation needs to be evaluated. Using the SIV macaque model, we set out to study the impact of underlying infection with HSV-2 or treatment with the adjuvant polyICLC on rectal immunization with the live attenuated vaccine SIV{Delta}Nef. We found that neither stimulus impacted complete protection from SIV; however, the combination of HSV-2 and polyICLC improved control of infection in animals that were not completely protected. Compared with non-controller macaques, controllers had less inflammatory T cells before SIV challenge as well as greater gene expression of IFN and more functional SIV-specific T cells after infection. The results add to our understanding of the mechanisms of SIV{Delta}Nef protection and demonstrate that mucosal immune activation does not necessarily undermine protection in mucosal vaccination against HIV.

immunology↗

bioRxiv2017

Phencyclidine discoordinates hippocampal network activity but not place fields

We used the psychotomimetic phencyclidine (PCP) to investigate the relationships between cognitive behavior, coordinated neural network function and information processing within the hippocampus place cell system. We report in rats that PCP (5mg/kg i.p.) impairs a well-learned hippocampus-dependent place avoidance behavior in rats that requires cognitive control, even when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium and slow gamma oscillations in CA1 local field potentials (LFP) such that medium gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP but the drug discoordinates the sub-second temporal organization of discharge amongst place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations, despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the sub-second timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as the root of PCP-induced cognitive impairment.\n\nSIGNIFICANCE STATEMENTHippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the local field potential, and the discharge of a subset of pyramidal neurons called \"place cells\" is spatially organized such that discharge is restricted to locations called a cells \"place field.\" Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge, without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition.

neuroscience↗