Biology subjects

Hasenstaub, A. R.

Publications and source records attributed to Hasenstaub, A. R..

11 recordsLinked to original sources

bioRxiv2025

Survey of hippocampal responses to sound in naive mice reveals widespread activation by broadband noise onsets

Recent studies suggest some hippocampal (HC) neurons respond to passively presented sounds in naive subjects, but the specificity and prevalence of these responses remain unclear. We used Neuropixels probes to record unit activity in HC and auditory cortex (ACtx) of awake, untrained mice during presentation of diverse sound stimuli. A subset of HC neurons exhibited reliable, short-latency responses to passive sounds, including tones and broadband noise. HC units showed evidence of tuning for tone frequency but not spectrotemporal features in continuous dynamic moving ripples. Across sound types, HC responses overwhelmingly occurred at stimulus onset; they quickly adapted to continuous sounds and did not respond at sound offset. Among all sounds tested, broadband noise was by far most effective at driving HC activity, with response prevalence scaling with increasing spectral bandwidth and density. Responses to noise were also far more common than visual flash stimuli. Sound-evoked face movements, quantified by total facial motion energy (FME), correlated with population-level HC activity, but many individual units responded regardless of movement, indicating both auditory and motor-related inputs. These results show that abrupt, acoustic events are sufficient to activate HC neurons in the absence of learning or behavioral engagement. This suggests a possible role for HC in detecting salient environmental changes and supports the idea that auditory inputs contribute directly to HC function. Given emerging links between hearing loss and dementia, these findings highlight a potential pathway by which auditory deafferentation could impact cognitive health.

neuroscience↗

bioRxiv2024

Integration of Transplanted Interneurons Over a New Period of Ocular Dominance Plasticity in Adult Mouse Visual Cortex

Cortical interneurons play an important role in mediating the juvenile critical period for ocular dominance plasticity in the mouse primary visual cortex. Previously, we showed that transplantation of cortical interneurons derived from the medial ganglionic eminence (MGE) opens a robust period of ocular dominance plasticity 33-35 days after transplantation into neonatal host visual cortex. The plasticity can be induced by transplanting either PV or SST MGE-derived cortical interneurons; it requires transplanted interneurons to express the vesicular GABAergic transporter; and it is manifested by changes to the host visual circuit. Here, we show that transplantation of MGE-derived cortical interneurons into the adult host visual cortex also opens a period of ocular dominance plasticity. The transplanted interneurons must be active to induce plasticity, and the neuronal activity and tuning of visually evoked responses in transplanted and host PV and SST interneurons are modulated by the locomotor state of the host. We also show that changes in activity over the period of plasticity induction are different between PV and SST interneurons but similar between host and transplanted interneurons of each type. The present findings demonstrate that the transplant-induced plasticity generated in adult visual cortex has many features in common with the role of these interneurons during the normal, juvenile critical period.

neuroscience↗

bioRxiv2024

Not all cross-modal responses are explained by face movements

The meaning and functions of cross-modal sensory processing in the cortex is at the center of an ongoing debate. While some studies claim that such responses reflect genuine multisensory integration, others argue they are mere artifacts of stimulus-evoked movement or changes in internal state. We examined this issue by measuring face movements and neural activity in awake mouse primary auditory cortex (A1) and primary visual cortex (V1) during visual and auditory stimulation. Visual stimuli rarely evoked face movements, A1 responses to visual input remained robust even in the absence of movement, and optogenetic silencing of V1 reduced A1 visual responses, confirming a sensory origin of these cross-modal responses. These findings directly challenge the argument that cross- modal responses are purely movement-driven and emphasize that rather than assuming all cross-modal effects are artifactual, researchers must rigorously test each case. HighlightsO_LIUnlike auditory stimuli, visual stimuli rarely evoke face movements C_LIO_LIFace movements explain sound-evoked firing in VC but not visually evoked firing in AC C_LIO_LISilencing VC suppresses visually evoked firing in AC C_LIO_LIThese results confirm a sensory (rather than motor) origin of these responses C_LI

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bioRxiv2024

Sst- and Vip-Cre mouse lines without age-related hearing loss

GABAergic interneurons, including somatostatin (SST) and vasoactive intestinal peptide (VIP) positive cells, play a crucial role in cortical circuit processing. Cre recombinase-mediated manipulation of these interneurons is facilitated by commercially available knock-in mouse strains such as Sst-IRES-Cre (Sst-Cre) and Vip-IRES-Cre (Vip-Cre). However, these strains are troublesome for hearing research because they are only available on the C57BL/6 genetic background, which suffer from early onset age-related hearing loss (AHL) due to a mutation of the Cdh23 gene. To overcome this limitation, we backcrossed Sst-Cre and Vip-Cre mice to CBA mice to create normal-hearing offspring with the desired Cre transgenes. We confirmed that in these "CBA Cre" lines, Cre drives appropriate expression of Cre-dependent genes, by crossing CBA Cre mice to Ai14 reporter mice. To assess the hearing capabilities of the CBA Cre mice, we measured auditory brainstem responses (ABRs) using clicks and tones. CBA Cre mice showed significantly lower ABR thresholds compared to C57 control mice at 3, 6, 9, and 12 months. In conclusion, our study successfully generated Sst-Cre and Vip-Cre mouse lines on the CBA background that will be valuable tools for investigating the roles of SST and VIP positive interneurons without the confounding effects of age-related hearing loss.

neuroscience↗

bioRxiv2023

The h-current controls cortical recurrent network activity through modulation of dendrosomatic communication

A fundamental feature of the cerebral cortex is the ability to rapidly turn on and off maintained activity within ensembles of neurons through recurrent excitation balanced by inhibition. Here we demonstrate that reduction of the h-current, which is especially prominent in pyramidal cell dendrites, strongly increases the ability of local cortical networks to generate maintained recurrent activity. Reduction of the h-current resulted in hyperpolarization and increase in input resistance of both the somata and apical dendrites of layer 5 pyramidal cells, while strongly increasing the dendrosomatic transfer of low (<20 Hz) frequencies, causing an increased responsiveness to dynamic clamp-induced recurrent network-like activity injected into the dendrites and substantially increasing the duration of spontaneous Up states. We propose that modulation of the h-current may strongly control the ability of cortical networks to generate recurrent persistent activity and the formation and dissolution of neuronal ensembles.

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bioRxiv2023

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Previously, we showed that loss of clustered gamma protocadherins (Pcdh{gamma}), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Here we show that the sole deletion of the Pcdh{gamma}c4 isoform, but not of the other 21 isoforms in the Pcdh{gamma} gene cluster, increased cIN cell death in mice during the normal period of programmed cell death. Viral expression of the Pcdh{gamma}c4 isoform rescued transplanted cINs lacking Pcdh{gamma} from cell death. We conclude that Pcdh{gamma}, specifically Pcdh{gamma}c4, plays a critical role in regulating the survival of cINs during their normal period of cell death. This demonstrates a novel specificity in the role of Pcdh{gamma} isoforms in cortical development.

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bioRxiv2021

Audiovisual task switching rapidly modulates sound encoding in mouse auditory cortex

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep layer neurons. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant probe stimuli during intertrial intervals evoked fewer spikes without impairing stimulus encoding, indicating that these attention influences generalized beyond training stimuli. Importantly, these spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant spiking in AC, and that the deepest cortical layers may serve as a hub for integrating extramodal contextual information.

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bioRxiv2021

Visual modulation of spectrotemporal receptive fields in mouse auditory cortex

Recent studies have established significant anatomical and functional connections between visual areas and primary auditory cortex (A1), which may be important for perceptual processes such as communication and spatial perception. However, much remains unknown about the microcircuit structure of these interactions, including how visual context may affect different cell types across cortical layers, each with diverse responses to sound. The present study examined activity in putative excitatory and inhibitory neurons across cortical layers of A1 in awake male and female mice during auditory, visual, and audiovisual stimulation. We observed a subpopulation of A1 neurons responsive to visual stimuli alone, which were overwhelmingly found in the deep cortical layers and included both excitatory and inhibitory cells. Other neurons for which responses to sound were modulated by visual context were similarly excitatory or inhibitory but were less concentrated within the deepest cortical layers. Important distinctions in visual context sensitivity were observed among different spike rate and timing responses to sound. Spike rate responses were themselves heterogeneous, with stronger responses evoked by sound alone at stimulus onset, but greater sensitivity to visual context by sustained firing activity following transient onset responses. Minimal overlap was observed between units with visual-modulated firing rate responses and spectrotemporal receptive fields (STRFs) which are sensitive to both spike rate and timing changes. Together, our results suggest visual information in A1 is predominantly carried by deep layer inputs and influences sound encoding across cortical layers, and that these influences independently impact qualitatively distinct responses to sound. Significance statementMultisensory integration is ubiquitous throughout the brain, including primary sensory cortices. The present study examined visual responses in primary auditory cortex, which were found in both putative excitatory and inhibitory neurons and concentrated in the deep cortical layers. Visual-modulated responses to sound were similarly observed in excitatory and inhibitory neurons but were more evenly distributed throughout cortical layers. Visual modulation moreover differed substantially across distinct sound response types. Transient stimulus onset spike rate changes were far less sensitive to visual context than sustained spike rate changes during the remainder of the stimulus. Spike timing changes were often modulated independently of spike rate changes. Audiovisual integration in auditory cortex is thus diversely expressed among cell types, cortical layers, and response types.

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bioRxiv2020

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death.

Cortical function critically depends on inhibitory/excitatory balance. GABAergic cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjusted-during a period of postnatal development - by programmed cell death (PCD). The mechanisms that regulate cIN elimination remain controversial. Here we show that genes in the protocadherin (Pcdh)-{gamma} gene cluster, but not in the Pcdh- or Pcdh-{beta} clusters, are required for survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-{gamma} deficient and wild type cINs during PCD were indistinguishable. Co-transplantation of wild type and Pcdh-{gamma} deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-{gamma} C3, C4, and C5. We conclude that Pcdh-{gamma}, and specifically {gamma}C3, {gamma}C4, and {gamma}C5, play a critical role in regulating cIN survival during the endogenous period of PCD. SignificanceGABAergic cortical inhibitory interneurons (cINs) in the cerebral cortex originate from the ventral embryonic forebrain. After a long migration, they come together with local excitatory neurons to form cortical circuits. These circuits are responsible for higher brain functions, and the improper balance of excitation/inhibition in the cortex can result in mental diseases. Therefore, an understanding of how the final number of cINs is determined is both biologically and, likely, therapeutically significant. Here we show that cell surface homophilic binding proteins belonging to the clustered protocadherin gene family, specifically three isoforms in the Pcdh-{gamma} cluster, play a key role in the regulation cIN programmed cell death. Co-transplantation of mutant and wild-type cINs shows that Pcdh-{gamma} genes have cell-autonomous and non-cell autonomous roles in the regulation of cIN cell death. This work will help identify the molecular mechanisms and cell-cell interactions that determine how the proper ratio of excitatory to inhibitory neurons is determined in the cerebral cortex.

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bioRxiv2019

Transplanted cells are essential for the induction but not the expression of cortical plasticity

Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived-eye. We transplanted MGE neurons expressing archaerhodopsin, closed one eyelid for 4-5 days, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.\n\nSignificance StatementInterneuron transplantation into mouse V1 creates a window of heightened plasticity which is quantitatively and qualitatively similar to the normal critical period, i.e. short-term occlusion of either eye markedly changes ocular dominance. The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the ocular dominance shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the ocular dominance shift.\n\nOne Sentence SummaryNeuronal transplants do not just grow and connect--they induce plasticity in the adult brain.

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bioRxiv2017

Distinct regulation of history-dependent responses by two cortical interneuron populations

Cortical responses to repeated stimuli are highly dynamic and rapidly adaptive. Such rapid changes are prominent in all sensory cortices, across which many aspects of circuitry are conserved. As an example, in the auditory cortex, preceding sounds can powerfully suppress responses to later, spectrally similar sounds - a phenomenon called forward suppression. Whether cortical inhibitory networks shape such suppression, or whether it is wholly regulated by common mechanisms such as synaptic depression or spike-frequency adaptation, is controversial. Here, we show that optogenetically suppressing somatostatin-positive interneurons reveals facilitation in neurons that are normally forward-suppressed. This is accompanied by a weakening of forward suppression, suggesting that these interneurons regulate the strength of forward interactions. In contrast, inactivating parvalbumin-positive interneurons does not change suppression strength, but does alter its frequency-dependence. These results establish a role of cortical inhibition in forward suppression and link specific aspects of rapid sensory adaptation to genetically distinct interneuron types.

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