Biology subjects

Bosch, P. J.

Publications and source records attributed to Bosch, P. J..

4 recordsLinked to original sources

bioRxiv2026

Neuronal ramping and theta power during freely-moving and head-fixed mouse interval timing.

An important paradigm to study executive function is interval timing, which requires participants to estimate a temporal interval, often with a motor response. Interval timing translates from rodents to humans and can model neurodegenerative and neuropsychiatric disease. Interval timing also has parallel, time-dependent neurophysiology in rodents and humans, including time-dependent linear changes in neuronal firing rates over a temporal interval (ramping activity) and low-frequency [~]4 Hz "theta" activity evoked by trial start and response. Despite these translational features, an important confound of interval timing is movement and motor preparation, as participants must report their estimates by planning a movement. To address this confound, we first trained a group of 7 mice in a freely-moving interval timing task in which mice had to move across an operant chamber and nosepoke at the correct time to receive food reward. These mice were then trained in a head-fixed version of interval timing in which mice receive liquid reward for holding still for 3 seconds at the correct location, with reward access randomized to probe interval timing behavior. Despite vastly different motor sequences, we found prominent ramping activity in mouse prefrontal cortex ensembles and prefrontal cortical [~]4 Hz activity evoked both by trial start and preceding the timed decision. These data provide evidence that prefrontal neuronal ramping and theta activity is not linked to a specific motor program but rather a feature of the temporal organization of behavior.

animal behavior and cognition↗

bioRxiv2023

Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex

Lewy Body Dementias (LBD), including Parkinsons disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

neuroscience↗

bioRxiv2021

p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Proper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded by Trp53, were consistently upregulated. Heterozygous deletion of Trp53 rescued neurodegeneration in Akirin2-null neurons. These data: 1) implicate Akirin2 as a critical neuronal maintenance protein; 2) identify p53 pathways as mediators of Akirin2 functions; and 3) suggest Akirin2 dysfunction may be relevant to neurodegenerative diseases.

neuroscience↗

bioRxiv2019

CRISPR/Cas9 interrogation of the mouse Pcdhg gene cluster reveals a crucial isoform-specific role for Pcdhgc4

The mammalian Pcdhg gene cluster encodes a family of 22 cell adhesion molecules, the gamma-Protocadherins ({gamma}-Pcdhs), critical for neuronal survival and neural circuit formation. The extent to which isoform diversity-a{gamma}-Pcdh hallmark-is required for their functions remains unclear. We used a CRISPR/Cas9 approach to reduce isoform diversity, targeting each Pcdhg variable exon with pooled sgRNAs to generate an allelic series of 26 mouse lines with 1 to 21 isoforms disrupted via discrete indels at guide sites and/or larger deletions/rearrangements. Analysis of 5 mutant lines indicates that postnatal viability and neuronal survival do not require isoform diversity. Surprisingly, as it is the only {gamma}-Pcdh that cannot independently engage in homophilic trans-interactions, we find that {gamma}C4, encoded by Pcdhgc4, is the only critical isoform. Because the human orthologue is the only PCDHG gene constrained in humans, our results indicate a conserved {gamma}C4 function that likely involves distinct molecular mechanisms.

developmental biology↗