Biology subjects

Jenks, K. R.

Publications and source records attributed to Jenks, K. R..

8 recordsLinked to original sources

bioRxiv2026

Eye-specific drive and binocular suppression in mouse visual cortex during critical period development

A key function of cortical sensory circuits is to integrate information from multiple sources to build a unified representation of the external environment. The binocular region of the mouse primary visual cortex (bV1) is a valuable model for studying sensory integration, as visual response properties of inputs from the contralateral (contra) and ipsilateral (ipsi) eye onto bV1 neurons become matched to one another over development. While the alignment of visual responses from each eye during this developmental critical period has been well-characterized, it remains unclear how this interocular alignment influences, and is influenced by, the binocularly driven responses of bV1 neurons. Here, we recorded the monocular and binocular visual response properties of layer 2/3 bV1 neurons by performing chronic two-photon calcium imaging at multiple time points spanning the ocular-dominance critical period. We found that ipsi driven responses strengthened in bV1 neurons alongside a concurrent increase in binocular suppression. Binocular tuning properties were more strongly aligned with contra responses than with ipsi responses throughout development but became progressively better matched to ipsi responses. Additionally, the explained variance of ipsi input to predicting binocular tuning increased. In chronically tracked bV1 neurons, the preferred orientation of ipsi eye driven responses was less stable than that of contra eye driven responses, and in well-tuned stable binocular neurons, ipsi and contra preferences became progressively better matched. Using population-based decoding analyses, we found that while monocular and binocular visual encoding remained stable, there was increased generalizability between visual encoding by binocular and ipsi eye driven responses. Overall, our data suggest a reciprocal interaction between ipsi development and binocular responses, such that ipsi visual inputs dynamically structure excitatory as well as putative inhibitory drive onto binocular neurons during the critical period to generate the circuitry that implements integrated binocular vision.

neuroscience↗

bioRxiv2026

Decomposing the modulation of interactions between neuronal populations

Identifying subpopulations of neurons that interact with each other from simultaneous recordings of populations of many neurons is key for understanding across-brain communication with cellular resolution. Recent work identified communication subspaces, which capture additive interactions between pairs of high-dimensional neural populations through a small number of source and target activity patterns. However, no current method captures how a third, potentially multivariate variable - such as behavioral state or the activity of a third population - modulates these interactions. Here we extend the communication subspace framework by parameterizing modulation as a low-rank tensor. This identifies multiplicative interaction channels (MICs), defined as triplets of source, target, and modulator activity patterns, in which the modulator pattern gates the source-target interaction. We derive MICs as a bilinear perturbation of reduced-rank regression. We develop a hierarchical fitting pipeline and provide a closed-form decomposition that quantifies whether modulation reshapes the modulator-averaged baseline interaction, recruits private dimensions of one population, or opens new interactions. In simulations, MICs reliably recover the presence and geometry of ground-truth modulation even in the high-dimensional, low-sample regime. Applying MICs to simultaneous calcium imaging of prefrontal axons and interneurons in the visual cortex revealed that behavioral state asymmetrically modulates top-down interactions, reconfiguring the patterns of prefrontal projections that interact with a stable set of visual interneuron activity patterns. By providing an efficient and compact characterization of modulatory interactions, MICs enable asking new questions about how potentially high-dimensional variables shape interactions between neural populations.

neuroscience↗

bioRxiv2026

nELAVL phosphorylation by CDKL5 regulates inter-condensates composition and communication to promote experience-dependent maturation of the visual cortex

Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos, resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.

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bioRxiv2024

Cortical norepinephrine-astrocyte signaling critically mediates learned behavior

Updating behavior based on feedback from the environment is a crucial means by which organisms learn and develop optimal behavioral strategies1-3. Norepinephrine (NE) release from the locus coeruleus (LC) has been shown to mediate learned behaviors4-6 such that in a task with graded stimulus uncertainty and performance, a high level of NE released after an unexpected outcome causes adaptations in subsequent behavior7. Yet, how the transient activity of LC-NE neurons, lasting tens of milliseconds, alters neuronal activity and influences behavior several seconds later is unclear. Here, we show that NE released after an unexpected outcome acts directly on cortical astrocytes via 1 adrenergic (Adra1a) receptors to elicit sustained increases in intracellular calcium. Chemogenetic blockade of astrocytic calcium dynamics prevents trial-to-trial behavioral adaptation. NE stimulation of astrocytes elicits ATP release, and imaging ATP levels in the cortex reveals an increase in extracellular ATP in response to an unexpected outcome. Blocking ATP-driven signaling to neuronal adenosine A1 receptors also prevents post-reinforcement behavioral adaptation. Finally, high density neuronal recordings in prefrontal cortex reveal that a surprising outcome alters the neuronal representation of the stimulus on the subsequent trial without sustained changes in cortical activity; blocking either astrocyte calcium dynamics or A1 receptors occludes these post-reinforcement changes in single-neuron and population neuronal encoding of task variables underlying behavioral changes. Together, these data demonstrate that astrocytes play an essential role in norepinephrine-driven learned behavior: they have prolonged calcium responses to transient norepinephrine release and convey task-relevant reinforcement information across behavioral intervals, enabling selective updating of neuronal task representations to support adaptive behavior.

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bioRxiv2024

Prefrontal Cortex subregions provide distinct visual and behavioral feedback modulation to the Primary Visual Cortex

The mammalian Prefrontal Cortex (PFC) has been suggested to modulate sensory information processing across multiple cortical regions via long-range axonal projections. These axonal projections arise from PFC subregions with unique brain-wide connectivity and functional repertoires, which may provide the architecture for modular feedback intended to shape sensory processing. Here, we used axonal tracing, axonal and somatic 2-photon calcium imaging, and chemogenetic manipulations in mice to delineate how projections from the Anterior Cingulate Cortex (ACA) and ventrolateral Orbitofrontal Cortex (ORB) of the PFC modulate sensory processing in the primary Visual Cortex (VISp) across behavioral states. Structurally, we found that ACA and ORB had distinct patterning of projections across cortical regions and layers, monosynaptically targeting both excitatory and inhibitory neuronal cell types in these areas. ACA axons in VISp had a stronger representation of visual stimulus information than ORB axons, but both projections showed non-visual, behavior-dependent activity. ACA input to VISp enhanced the encoding of visual stimuli by VISp neurons, and modulation of visual responses scaled with arousal. On the other hand, ORB input shaped movement and arousal related modulation of VISp visual responses, but surprisingly reduced the encoding of high-contrast visual stimuli. Thus, ACA and ORB feedback have separable projection patterns and encode distinct visual and behavioral information, putatively providing the substrate for their unique effects on visual representations and behavioral modulation in VISp. Our results offer a refined model of cortical hierarchy and its impact on sensory information processing, whereby specific PFC projections contribute uniquely to VISp activity during discrete behavioral states.

neuroscience↗

bioRxiv2024

The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex

Circular RNAs (circRNAs) are a class of closed-loop, single stranded RNAs whose expression is particularly enriched in the brain. Despite this enrichment and evidence that the expression of circRNAs are altered by synaptic development and in response to synaptic plasticity in vitro, the regulation by and function of the majority of circRNAs in experience-dependent plasticity in vivo remain unexplored. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of experience-dependent developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent mRNA forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following 3-day MD. Knockdown of circHomer1 delayed the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown also led to a reduction in average dendritic spine size prior to MD but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 knockdown impairs experience-dependent AMPA receptor endocytosis. Thus, the expression of multiple circRNAs are regulated by experience-dependent developmental plasticity, and our findings highlight the essential role of circHomer1 in V1 synaptic development and experience-dependent plasticity. Significance StatementCircular RNAs (circRNAs) are a class of closed-loop RNAs formed through back-splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in experience-dependent plasticity remains poorly understood. We conducted an in vivo transcriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in the mouse visual cortex and highlight circHomer1, a circRNA derived from the Homer1 gene, as a circRNA critical for synaptic development and experience-dependent plasticity in vivo.

neuroscience↗

bioRxiv2019

Experience-dependent development and maintenance of binocular neurons in the mouse visual cortex

The normal development of neuronal circuits requires both hard-wired gene expression and experience. Sensory processing, such as vision, is especially sensitive to perturbations in experience. However, the exact contribution of experience to neuronal visual response properties and binocular vision remains unknown. To determine how visual response properties develop in vivo, we used single cell resolution two-photon calcium imaging of mouse binocular visual cortex at multiple time-points after eye opening. Few neurons are binocularly responsive immediately after eye opening and respond solely to either the contralateral or ipsilateral eye. Binocular neurons emerge during development, which requires visual experience, and show specific tuning of visual response properties. As binocular neurons emerge, activity between the two eyes becomes more correlated in the neuropil. Since experience-dependent plasticity requires the expression of activity-dependent genes, we determined whether the plasticity gene Arc mediates the development of normal visual response properties. Surprisingly, rather than mirroring the effects of visual deprivation, mice that lack Arc show increased numbers of binocular neurons during development. Strikingly, removing Arc in adult binocular visual cortex increases the numbers of binocular neurons and recapitulates the developmental phenotype, suggesting cortical circuits that mediate visual processing require ongoing experience-dependent plasticity. Thus, experience is critical for the normal development and maintenance of circuits required to process binocular vision.

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bioRxiv2017

Arc Restores Juvenile Plasticity In Adult Mouse Visual Cortex

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation (MD) during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression, and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.\n\nSignificance StatementNeuronal plasticity peaks early in life during critical periods and normally declines with age, but the molecular changes that underlie this decline are not fully understood. Using the mouse visual cortex as a model, we found that activity-dependent expression of the neuronal protein Arc peaks early in life, and that loss of activity-dependent Arc expression parallels loss of synaptic plasticity in the visual cortex. Genetic overexpression of Arc prolongs the critical period of visual cortex plasticity and acute viral expression of Arc in adult mice can restore juvenile-like plasticity. These findings provide a mechanism for the loss of excitatory plasticity with age, and suggest that Arc may be an exciting therapeutic target for modulation of the malleability of neuronal circuits.

neuroscience↗