Biology subjects

Vicini, S.

Publications and source records attributed to Vicini, S..

8 recordsLinked to original sources

bioRxiv2025

MMP-2/9 inhibition modulates sharp wave abundance, inhibitory proteoglycan sulfation, and fear memory in juvenile zebrafish: relevance to affective disorders

Sharp wave ripple (SWR) events, present in diverse species, spontaneously occur in the hippocampus during quiescent restfulness and slow-wave sleep. SWRs comprise a negative deflection, the sharp wave (SW) event with an often-superimposed ripple (R) and are the neural correlates of memory consolidation and recall. The Anterodorsolateral lobe (ADL) (zebrafish hippocampal homologue) exhibits SW and SWR events, and since SWs initiate SWRs, their abundance typically shows the same directionality. In previous work, we observed matrix metalloproteinase-9 (MMP-9)-dependent effects on depression-relevant behaviors, perineuronal net (PNN) levels, and SWR abundance in the adult rodent hippocampus. Here, we investigate MMP-2/9-dependent effects on biochemical, behavioral, and neurophysiological endpoints in juvenile zebrafish and zebrafish at the transition from the late juvenile period to early adulthood. With MMP-2/9 inhibition, juvenile zebrafish showed reduced SW amplitude and abundance together with increased fear memory retention and reduced sociability. Juvenile zebrafish also showed an increased percentage of longer-duration SW events. Except for a reduction in SW amplitude, these changes were not observed at the transition from late juvenile to early adulthood. These changes were accompanied by increased levels of chondroitin sulfate (CS) proteoglycan 4-O-sulfation, which modulates PNNs and excitatory-to-inhibitory (E/I) balance. Discontinuation of MMP-2/9 inhibition in juvenile zebrafish normalized deficits in ADL SW abundance and sociability. Together, these findings show that MMP-2/9 significantly influences E/I balance and learning and memory during the highly plastic juvenile period in zebrafish. Findings also have relevance to an emerging appreciation of PNN changes that may contribute to altered neuronal oscillations and mood or cognition.

neuroscience↗

bioRxiv2024

Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice

Current therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks of cellular senescence, which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models. It is unknown whether SC accumulation contributes to epileptogenesis and associated cognitive impairments. To address this question, we used a mouse model of temporal lobe epilepsy (TLE) and characterized the senescence phenotype throughout epileptogenesis. SCs accumulated 2 weeks after SE and were predominantly microglia. We ablated SCs and reduced (and in some cases prevented) the emergence of spontaneous seizures and normalized cognitive function in mice. Suggesting that this is a translationally-relevant target we also found SC accumulation in resected hippocampi from patients with TLE. These findings indicate that SC ablation after an epileptogenic insult is a potential anti-epileptogenic therapy.

neuroscience↗

bioRxiv2024

Cryptic recombination and transposition drive structural variation to shape genomic plasticity and life history traits in a host generalist fungal plant pathogen

BackgroundAn understanding of plant pathogen evolution is important for sustainable management of crop diseases. Plant pathogen populations must maintain adequate heritable phenotypic variability to survive. Polymorphisms >= 50 bp, known as structural variants (SVs), could contribute strongly to this variability by disrupting gene activities. SV acquisition is largely driven by mobile genetic elements called transposons, though a less appreciated source of SVs is erroneous meiotic double-strand break repair. The relative impacts of transposons and recombination on SV diversity and the overall contribution of SVs to phenotypic variability is elusive, especially in host generalists. ResultsWe use 25 high quality genomes to create a graphical pan-genome of the globally distributed host-generalist crop pathogen Sclerotinia sclerotiorum. Outcrossing and recombination rates in this self-fertile species have been debated. Using bisulfite sequencing, and short read data from 190 strains, we show that S. sclerotiorum has many hallmarks of eukaryotic meiosis, including recombination hot and cold spots, centromeric and genic recombination suppression, and rapid linkage disequilibrium decay. Using a new statistic that captures average pairwise structural variation, we show that recombination and transposons make distinct contributions to SV diversity. Furthermore, despite only 5 % of genes being dispensable, SVs often had a stronger impact than other variants across 14 life history traits measured in 103 distinct strains. ConclusionTransposons and recombination make distinct contributions to SV diversity in S. sclerotiorum. Despite limited gene content diversity, SVs may strongly impact phenotypic variability. This sheds light on the genomic forces shaping adaptive flexibility in host generalists.

genomics↗

bioRxiv2024

Neuronal subtypes and connectivity of the adult mouse paralaminar amygdala

The paralaminar nucleus of the amygdala (PL) is comprised of neurons which exhibit delayed maturation. PL neurons are born during gestation but mature during adolescent ages, differentiating into excitatory neurons. The PL is prominent in the adult amygdala, contributing to its increased neuron number and relative size compared to childhood. However, the function of the PL is unknown, as the region has only recently begun to be characterized in detail. In this study, we investigated key defining features of the adult PL; the intrinsic morpho-electric properties of its neurons, and its input and output connectivity. We identify two subtypes of excitatory neurons in the PL based on unsupervised clustering of electrophysiological properties. These subtypes are defined by differential action potential firing properties and dendritic architecture, suggesting divergent functional roles. We further uncover major axonal inputs to the adult PL from the main olfactory network and basolateral amygdala. We also find that axonal outputs from the PL project reciprocally to major inputs, and to diverse targets including the amygdala, frontal cortex, hippocampus, hypothalamus, and brainstem. Thus, the adult PL is centrally placed to play a major role in the integration of olfactory sensory information, likely coordinating affective and autonomic behavioral responses to salient odor stimuli. Significance StatementMammalian amygdala development includes a growth period from childhood to adulthood, believed to support emotional and social learning. This amygdala growth is partly due to the maturation of neurons during adolescence in the paralaminar amygdala. However, the functional properties of these neurons are unknown. In our recent studies, we characterized the paralaminar amygdala in the mouse. Here, we investigate the properties of the adult PL in the mouse, revealing the existence of two neuronal subtypes that may play distinct functional roles in the adult brain. We further reveal the brain-wide input and output connectivity of the PL, indicating that the PL combines olfactory cues for emotional processing and delivers information to regions associated with reward and autonomic states.

neuroscience↗

bioRxiv2023

Sharp wave ripple coupling in zebrafish hippocampus and basolateral amygdala

The mammalian hippocampus exhibits sharp wave events (1-30 Hz) with an often-present superimposed fast ripple oscillation (120-200 Hz) forming a sharp wave ripple (SWR) complex. During slow wave sleep or consummatory behaviors, SWRs result from the sequential spiking of hippocampal cell assemblies initially activated during imagined or learned experiences. SWRs occur in tandem with cortical/subcortical assemblies critical to the long-term storage of specific memory types. Leveraging juvenile zebrafish, we show that SWR events in their hippocampal homologue, the anterodorsolateral lobe (ADL), in ex vivo whole-brains are locally generated and maintained. SWR events were also recorded in the basolateral amygdala (BLA). Concomitant single cell calcium imaging and local field potential (LFP) recordings showed that BLA SWs couple to ADL SWs. Calcium imaging recordings of whole-brains demonstrated that ADL and BLA SWRs are endogenously and spontaneously silenced by the activation of a more caudal population of putative cholinergic cells. Electrical stimulation of this caudal region silenced ADL SWs. Our results suggest that the SWR-generating circuit is evolutionarily conserved through shared acetylcholine modulating mechanisms. These findings further our understanding of neuronal population dynamics in the zebrafish brain and highlights their advantage for simultaneously recording SW/SWRs and single cell activity in diverse brain regions.

neuroscience↗

bioRxiv2020

Inhibitory parvalbumin basket cells are selectively impaired during hippocampal sharp wave ripples in a mouse model of familial Alzheimer's disease

Memory disruption in mild cognitive impairment (MCI) and Alzheimers disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the micro-circuitry underlying these disruptions is under-explored. We tested if a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female 3-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs having a higher probability of spiking during SWRs. Both deep and superficial PCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC micro-circuit also contribute to impairment. Significance StatementWe demonstrate that a specific sub-type of inhibitory neuron, parvalbumin-expressing basket cells, have selectively reduced activity in a model of Alzheimers disease during activity critical for the consolidation of memory. These results identify a potential cellular target for therapeutic intervention to restore aberrant network activity in early amyloid pathology. While parvalbumin cells have previously been identified as a potential therapeutic target, this study for the first time recognizes that other parvalbumin neuronal sub-types, including bistratified and axo-axonic cells, are spared. These experiments are the first to record synaptic and spiking activity during sharp wave ripple events in early amyloid pathology and reveal that a selective decrease in excitatory synaptic drive to parvalbumin basket cells likely underlies reduced function.

neuroscience↗

bioRxiv2018

Measurements of Subthreshold and Fast Population Neuronal Activity with Genetically Encoded Calcium Indicator GCaMP-6f

GCaMP-6f is among the best calcium indicators and has been widely used for monitoring neuronal activity in the brain. Applications are at cellular level (calcium transients of action potentials) or population activity (fluorimetry) during network events. Two important issues remain less explored: 1) Is GCaMP-6f signal sensitive enough for detecting subthreshold activity, similar to the sensitivity of local field potential (LFP)? 2) Is the GCaMP-6f signal fast enough for detecting network oscillations seen in LFP? Here the two issues are explored in a number of network events including hippocampus sharp waves (SWs), carbachol induced theta oscillations, interictal-like spikes and neuronal response evoked by high frequency stimuli. SWs are a typical network event with the majority of neurons receiving subthreshold excitatory or inhibitory synaptic input without firing action potentials. The excitatory/inhibitory post synaptic potentials (EPSP/IPSP) in the neuropil become detectable in local field potential (LFP) signals. We compare simultaneously recorded LFP and optical recording of GCaMP-6f fluorescent signals in Thy1-GCaMP-6f mice hippocampal slices. We found that the occurrence of SWs produces a clear population GCaMP-6f signal of 0.3% dF/F. This population GCaMP-6f signal correlated well with the LFP, albeit a delay of ~50 ms was observed. The population GCaMP-6f signal follows well with the 20 Hz population activity evoked by electric stimuli, while activity up to 40 Hz was detected with reduced amplitude. GCaMP-6f and LFP signals showed a large amplitude discrepancy. The amplitude of GCaMP increased ~1000 times from SW to carbachol induced theta burst, while the LFP changed less than 10 times. Our results suggested that population GCaMP-6f signals may become a sensitive tool for detecting network activity, especially for that with low LFP amplitude during elevated spiking rate but asynchronized events. GCaMP signal is fast enough for monitoring theta and beta oscillations (<25Hz) in the neuronal population. Faster calcium indicators (e.g., GCaMP-7) may improve the frequency response property for detecting gamma band oscillations. In addition, population GCaMP recordings are non-contact and free from stimulation artifacts. These features may be useful for high throughput recordings and applications sensitive to stimulus artifact, e.g., monitoring response during continuous stimulations.

neuroscience↗

bioRxiv2017

Disruption of perineuronal nets increases the frequency of sharp wave ripples

Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training-associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells and require initial excitation of CA1 pyramidal cells as well as subsequent participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of pyramidal cells thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of 490 micron horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1. As compared to vehicle, pretreatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pretreatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events.

neuroscience↗