Biology subjects

Hackett, T. A.

Publications and source records attributed to Hackett, T. A..

6 recordsLinked to original sources

bioRxiv2026

Noise-induced temporary threshold shift in macaques disrupts electrophysiological temporal processing despite recovery of cochlear sensitivity and preserved ribbon synapse counts

Noise exposure can produce lasting auditory dysfunction in the absence of permanent threshold shifts or hair cell loss, yet the functional consequences of temporary threshold shift (TTS) remain poorly defined in translational models. We assessed auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in rhesus macaques (n = 13) at 2 and 9-10 months following a single moderate noise exposure that induced TTS. Previous histological analyses of these macaques showed no significant loss of hair cells or ribbon synapses but revealed persistent broadening of inner and outer hair cell ribbon-volume distributions. After exposure, DPOAE amplitudes and thresholds and ABR thresholds returned to pre-exposure values and showed low-frequency enhancement at later time points. Suprathreshold click- and tone-evoked ABR amplitudes were largely preserved or enhanced after exposure, consistent with compensatory gain. In contrast, macaque-specific chirp-evoked ABRs showed modest amplitude reductions and latency prolongation across waves, indicating altered neural synchrony at standard stimulus presentation rates, but with variable time courses. More temporally demanding paradigms revealed persistent impairments. ABRs to faster click rates and shorter paired-click intervals showed reduced adaptability in response amplitude and timing after normalization, with deficits persisting through 9-10 months. Increased inner hair cell ribbon-volume variability was more consistently associated with temporal response measures, including latency, paired-click recovery, and rate adaptation, than with amplitude-based ABR measures. Together, these findings reveal a lasting dissociation between response magnitude and fidelity after TTS: suprathreshold responses may be preserved or enhanced, while neural synchrony and temporal adaptability remain impaired. Increased presynaptic ribbon volume variability may serve as a structural marker of synaptic remodeling accompanying hidden auditory dysfunction, rather than as a direct determinant of suprathreshold response magnitude. Temporally demanding ABR paradigms may supplement threshold-based diagnostics for detecting persistent noise-induced auditory dysfunction.

neuroscience↗

bioRxiv2026

Persistent impairment of spatial hearing and neural binaural interaction after temporary noise-induced hearing loss

Many people have trouble understanding speech in noisy environments despite normal audiometric thresholds, a condition referred to as "hidden hearing loss." A leading hypothesis attributes this deficit to inner hair cell synaptic pathology (cochlear synaptopathy), which can persist after recovery from noise-induced temporary elevation of audiometric thresholds. This pathology impairs the temporally precise sound encoding necessary for spatial hearing, but direct evidence in primates, human or nonhuman, is lacking. Here, we show that a single noise exposure, producing only a temporary threshold elevation, induced long-lasting alterations in synaptic morphology, without synapse loss, resulting in persistent spatial hearing deficits for up to 11 months post-exposure in nonhuman primates of both sexes. These perceptual deficits were accompanied by a reduction in a neurophysiological measure of binaural processing - the binaural interaction component (BIC) of the auditory brainstem response (ABR). Both behavioral and neural deficits persisted despite full recovery of audiometric thresholds. Together, these findings provide the first evidence in primates that noise exposure disrupts spatial hearing and binaural neural circuit function without loss of hair cells or synapses. Because spatial hearing tests and the ABR/BIC are clinically accessible, this work also establishes translational biomarkers for early neural dysfunction underlying hidden hearing loss.

neuroscience↗

bioRxiv2025

Cochlear histopathology in macaques after noise-induced temporary threshold shifts

Noise exposures causing transient hearing loss were previously considered benign. However, recent work has revealed that temporary noise-induced threshold shifts may be associated with long-lasting cochlear histopathology. One such effect is cochlear synaptopathy, i.e. changes to the afferent synapse between inner hair cells and auditory nerve fibers. Noise-induced synaptopathy has been extensively characterized in several rodent models, and temporal bone studies suggest similar age-related changes in humans. However, it remains unclear how noise-induced temporary threshold shifts affect cochlear structures in humans and nonhuman primates, which show greater resistance to noise exposure than other animals. Additionally, the long-term sequelae of temporary threshold shifts are largely unknown. Here, we characterized the effects of a noise exposure causing temporary hearing loss on cochlear histopathology in macaque monkeys at long post-exposure survival times. Overall, cochlear histopathology was variable across subjects, similar to the variable susceptibility observed in humans. At 2 and 10 months post-exposure, macaques had no significant loss of hair cells, inner hair cell synapses, or cholinergic efferent innervation. However, enlargement of ribbons in both inner and outer hair cells was observed. Together, these findings provide insight into the cochlear effects of single-exposure temporary threshold shifts in nonhuman primates. HIGHLIGHTS- Macaques exposed to 120 dB SPL noise for 4h showed temporary threshold shifts - Cochlear histopathology was evaluated at 2 and 10 months post-exposure - Macaques had no significant loss of hair cells or inner hair cell synapses - Chronic enlargement of inner and outer hair cell ribbons was observed - Transient loss of outer hair cell ribbons was also observed

neuroscience↗

bioRxiv2025

Layer 6 is a hub for cholinergic modulation in the mouse auditory cortex

AbstractBasal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Several studies have shown that acetylcholine (ACh) rapidly modifies local cortical circuits via nicotinic ACh receptors (nAChRs) on layer 1 (L1) inhibitory neurons. BFCN terminals are also abundant in L6, though the mechanisms and functional consequences of cholinergic modulation in deeper cortical layers has received less attention. Here, we performed multi-plex in situ labeling across cortical layers and cell types and found that L6 pyramidal neurons (L6-PNs) were highly enriched in diverse nAChR subunit and muscarinic ACh receptor (mAChR) transcripts. In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking (RS) units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast excitatory post-synaptic potentials via nAChRs in L6-PNs, comparable to responses in L1-INs, and slower inhibitory responses mediated by mAChRs. These findings identify L1 inhibitory neurons and L6 excitatory neurons as two hubs that mediate BFCN modulation of cortical circuits. Transcriptional, synaptic, and local circuit connectivity differences between L1 and L6 hubs may allow BFCN inputs to shape perception and plasticity on distinct timescales.

neuroscience↗

bioRxiv2023

Recurrent activity within microcircuits of macaque dorsolateral prefrontal cortex tracks cognitive flexibility

Human and non-human primate data clearly implicate the dorsolateral prefrontal cortex (dlPFC) as critical for advanced cognitive functions1,2. It is thought that intracortical synaptic architectures within dlPFC are the integral neurobiological substrate that gives rise to these processes, including working memory, inferential reasoning, and decision-making3-7. In the prevailing model, each cortical column makes up one fundamental processing unit composed of dense intrinsic connectivity, conceptualized as the canonical cortical microcircuit3,8. Each cortical microcircuit receives sensory and cognitive information from a variety of sources which are represented by sustained activity within the microcircuit, referred to as persistent or recurrent activity4,9. Via recurrent connections within the microcircuit, activity can propagate for a variable length of time, thereby allowing temporary storage and computations to occur locally before ultimately passing a transformed representation to a downstream output4,5,10. Competing theories regarding how microcircuit activity is coordinated have proven difficult to reconcile in vivo where intercortical and intracortical computations cannot be fully dissociated5,9,11,12. Here, we interrogated the intrinsic features of isolated microcircuit networks using high-density calcium imaging of macaque dlPFC ex vivo. We found that spontaneous activity is intrinsically maintained by microcircuit architecture, persisting at a high rate in the absence of extrinsic connections. Further, using perisulcal stimulation to evoke persistent activity in deep layers, we found that activity propagates through stochastically assembled intracortical networks, creating predictable population-level events from largely non-overlapping ensembles. Microcircuit excitability covaried with individual cognitive performance, thus anchoring heuristic models of abstract cortical functions within quantifiable constraints imposed by the underlying synaptic architecture.

neuroscience↗

bioRxiv2022

Increased Pyramidal and VIP Neuronal Excitability in Primary Auditory Cortex Directly Correlates with Tinnitus Behavior

Tinnitus affects roughly 15-20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage to the auditory periphery, resulting in a cascade of maladaptive plastic changes at multiple levels of the central auditory neuraxis as well as limbic and non-auditory cortical centers. Using a well-established condition-suppression model of tinnitus, we measured tinnitus-related changes in the microcircuits of excitatory/inhibitory neurons onto layer 5 pyramidal neurons (PNs), as well as changes in the excitability of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1). Patch-clamp recordings from PNs in A1 slices showed tinnitus-related increases in spontaneous excitatory postsynaptic currents (sEPSCs) and decreases in spontaneous inhibitory postsynaptic currents (sIPSCs). Both measures were directly correlated to the rats behavioral evidence of tinnitus. Tinnitus-related changes in PN excitability were independent of changes in A1 excitatory or inhibitory cell numbers. VIP neurons, part of an A1 local circuit that can disinhibit layer 5 PNs, showed significant tinnitus-related increases in excitability that directly correlated with the rats behavioral tinnitus score. That PN and VIP changes directly correlated to tinnitus behavior, suggests an essential role in A1 tinnitus pathology. Tinnitus-related A1 changes were similar to findings in studies of neuropathic pain in somatosensory cortex suggesting a common pathology of these troublesome perceptual impairments. Improved understanding between excitatory, inhibitory and disinhibitory sensory cortical circuits can serve as a model for testing therapeutic approaches to the treatment of tinnitus and chronic pain. Key pointsO_LIIdentify tinnitus-related changes in synaptic function of specific neuronal subtypes in a reliable animal model of tinnitus. C_LIO_LIFinding show direct and indirect tinnitus-related losses of normal inhibitory function at A1 layer 5 pyramidal cells, and increased VIP excitability. C_LIO_LIFindings are similar to what has been shown for neuropathic pain suggesting that restoring normal inhibitory function at synaptic inputs onto A1 pyramidal neurons could conceptually reduce tinnitus discomfort. C_LI

neuroscience↗