Biology subjects

Geffen, M. N.

Publications and source records attributed to Geffen, M. N..

15 recordsLinked to original sources

bioRxiv2025

The role of inhibitory neurons in novelty sound detection in regular and random statistical contexts.

Detecting statistical regularities in sound and responding to violations of these patterns, termed deviance detection, is a core function of the auditory system. In the human brain, studies have shown that deviance responses are enhanced in regular compared to random auditory contexts, but the underlying neuronal circuit mechanisms remain unclear. Here, we examined how inhibitory neurons contribute to context-dependent deviance responses in mouse auditory cortex (AC). Using two-photon calcium imaging in AC of awake head-fixed male and female mice, we recorded neuronal activity during presentation of spectro-temporally rich moving ripple sounds, with deviant ripples embedded in either regular or random ripple sequences. AC neurons exhibited stronger responses to deviant sounds in regular contexts compared to random ones. To identify circuit mechanisms, we selectively inactivated parvalbumin (PV), somatostatin (SST), or vasoactive intestinal polypeptide (VIP) inhibitory neurons during the deviant stimulus presentation. Inactivation of PV and SST neurons broadly increased deviance responses in both contexts. In contrast, VIP inactivation selectively reduced responses to deviant stimuli in the regular, but not random, context, decreasing the context-dependent deviance signal enhancement. At the population level, inactivating all three neuronal subtypes increased detectability of the deviant stimulus, but the effects were context-dependent only for VIP inactivation. These findings reveal a distinct role for VIP neurons in modulating deviance signals based on context regularity, identifying a specific inhibitory neuron type that is critical for context-sensitive auditory processing and predictive coding. SIGNIFICANCE STATEMENTUnderstanding how the brain detects and responds to predictable and unexpected sounds is critical for communication and navigation in complex acoustic environments. Although prior studies have shown that detection of novel sounds is enhanced by regularity in background sound patterns, the underlying circuit mechanisms have remained unknown. Here, we find that neurons in the auditory cortex exhibit stronger deviance responses when the deviant sounds are embedded in regular, predictable sound sequences as compared to random sound sequences. Importantly, we identify a distinct role for specific inhibitory neurons in modulating this context-dependent enhancement. These findings reveal a new insight into how cortical circuits implement predictive coding strategies to optimize sensory processing.

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bioRxiv2024

Individual-specific strategies inform category learning

Categorization is an essential task for sensory perception. Individuals learn category labels using a variety of strategies to ensure that sensory signals, such as sounds or images, can be assigned to proper categories. Categories are often learned on the basis of extreme examples, and the boundary between categories can differ among individuals. The trajectories for learning also differ among individuals, as different individuals rely on different strategies, such as repeating or alternating choices. However, little is understood about the relationship between individual learning trajectories and learned categorization. To study this relationship, we trained mice to categorize auditory stimuli into two categories using a two-alternative forced choice task. Because the mice took several weeks to learn the task, we were able to quantify the time course of individual strategies and how they relate to how mice categorize stimuli around the categorization boundary. Different mice exhibited different trajectories while learning the task. Mice displayed preferences for a specific category, manifested by a choice bias in their responses, but this bias drifted with learning. We found that this drift in choice bias correlated with variability in the category boundary for sounds with ambiguous category membership. Next, we asked how stimulus-independent, individual-specific strategies informed learning. We found that the tendency to repeat choices, which is a form of perseveration, contributed to long-term learning. These results indicate that long-term trends in individual strategies during category learning affect learned category boundaries.

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bioRxiv2024

Direct piriform-to-auditory cortical projections shape auditory-olfactory integration

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory-olfactory integration using anatomical, electrophysiological, and optogenetic approaches, focusing on the auditory cortex as a key locus for cross-modal integration. First, retrograde and anterograde viral tracing strategies revealed a direct projection from the piriform cortex to the auditory cortex. Next, using in vivo electrophysiological recordings of neuronal activity in the auditory cortex of awake male or female mice, we found that odors modulate auditory cortical responses to sound. Finally, we used in vivo optogenetic manipulations during electrophysiology to demonstrate that olfactory modulation in auditory cortex, specifically, odor-driven enhancement of sound responses, depends on direct input from the piriform cortex. Together, our results identify a novel role of piriform-to-auditory cortical circuitry in shaping olfactory modulation in the auditory cortex, shedding new light on the neuronal mechanisms underlying auditory-olfactory integration. Significance StatementAll living organisms exist within multisensory environments, yet there is a lack in our understanding of how the brain integrates multisensory information. This work highlights a direct piriform-to-auditory cortical circuit governing auditory-olfactory integration. Our results shed new light on a relatively understudied area of multisensory research, promising a more robust understanding of how animals and humans perceive and interact within complex environments.

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bioRxiv2024

Cell-specific inhibitory modulation of sound processing in the auditory thalamus.

Inhibition plays an important role in controlling the flow and processing of auditory information throughout the central auditory pathway, yet how inhibitory circuits shape auditory processing in the medial geniculate body (MGB), the key region in the auditory thalamus, is poorly understood. The MGB gates the flow of auditory information to the auditory cortex, and it is inhibited largely by the thalamic reticular nucleus (TRN). The TRN contains two major classes of inhibitory neurons: parvalbumin (PVTRN)-positive and somatostatin (SSTTRN)-positive neurons. PV and SST neurons have been shown to play differential roles in controlling sound responses in auditory cortex. In the somatosensory and visual subregions of the TRN, PVTRN and SSTTRN neurons exhibit anatomical and functional differences. However, it remains unknown whether and how PVTRN and SSTTRN neurons differ in their anatomical projections from the TRN to the auditory thalamus, and whether and how they differentially modulate activity in the MGB. We find that PVTRN and SSTTRN neurons exhibit differential projection patterns within the auditory thalamus: PVTRN neurons predominantly project to ventral MGB, whereas SSTTRN neurons project to the dorso-medial regions of MGB. Optogenetic inactivation of PVTRN neurons bidirectionally modulated sound-evoked activity in MGB, increasing firing in 29% of MGB neurons, while suppressing firing in 41%. In contrast, inactivating SSTTRN neurons largely suppressed tone-evoked activity in MGB neurons. Cell type-specific computational models identified candidate circuit mechanisms for generating the differential effects of TRN inactivation on MGB sound responses. These distinct inhibitory pathways within the auditory thalamus reveal cell type-specific organization of thalamic inhibition in auditory computation.

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bioRxiv2023

Localist versus distributed representation of sounds in the auditory cortex controlled by distinct inhibitory neuronal subtypes

Cortical circuits contain multiple types of inhibitory neurons which shape how information is processed within neuronal networks. Here, we asked whether somatostatin-expressing (SST) and vasoactive intestinal peptide-expressing (VIP) inhibitory neurons have distinct effects on population neuronal responses to noise bursts of varying intensities. We optogenetically stimulated SST or VIP neurons while simultaneously measuring the calcium responses of populations of hundreds of neurons in the auditory cortex of male and female awake, head-fixed mice to sounds. Upon SST neuronal activation, noise bursts representations became more discrete for different intensity levels, relying on cell identity rather than strength. By contrast, upon VIP neuronal activation, noise bursts of different intensity level activated overlapping neuronal populations, albeit at different response strengths. At the single-cell level, SST and VIP neuronal activation differentially modulated the response-level curves of monotonic and nonmonotonic neurons. SST neuronal activation effects were consistent with a shift of the neuronal population responses toward a more localist code with different cells responding to sounds of different intensity. By contrast, VIP neuronal activation shifted responses towards a more distributed code, in which sounds of different intensity level are encoded in the relative response of similar populations of cells. These results delineate how distinct inhibitory neurons in the auditory cortex dynamically control cortical population codes. Different inhibitory neuronal populations may be recruited under different behavioral demands, depending on whether categorical or invariant representations are advantageous for the task. SIGNIFICANCEInformation about sounds is represented in the auditory cortex by neuronal population activity that has a characteristic sparse structure. Cortical neuronal populations comprise multiple types of excitatory and inhibitory neurons. Here, we find that activating different types of inhibitory neurons differentially controls population neuronal representations, with one type of inhibitory neurons increasing the differences in the identity of the cells recruited to represent the different sounds, and another inhibitory neuron type changing the relative activity level of overlapping neuronal populations. Such transformations may be beneficial for different types of auditory behaviors, suggesting that these different types of inhibitory neurons may be recruited under different behavioral constraints in optimizing neuronal representations of sounds.

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bioRxiv2022

The interplay of uncertainty, relevance and learning influences auditory categorization

Auditory perception requires categorizing sound sequences, such as speech or music, into classes, such as syllables or notes. Auditory categorization depends not only on the acoustic waveform, but also on variability and uncertainty in how the listener perceives the sound - including sensory and stimulus uncertainty, the listeners estimated relevance of the particular sound to the task, and their ability to learn the past statistics of the acoustic environment. Whereas these factors have been studied in isolation, whether and how these factors interact to shape categorization remains unknown. Here, we measured human participants performance on a multi-tone categorization task and modeled each participants behavior using a Bayesian framework. Task-relevant tones contributed more to category choice than task-irrelevant tones, confirming that participants combined information about sensory features with task relevance. Conversely, participants poor estimates of task-relevant tones or high-sensory uncertainty adversely impacted category choice. Learning the statistics of sound category over both short and long timescales also affected decisions, biasing the decisions toward the overrepresented category. The magnitude of this effect correlated inversely with participants relevance estimates. Our results demonstrate that individual participants idiosyncratically weigh sensory uncertainty, task relevance, and statistics over both short and long timescales, providing a novel understanding of and a computational framework for how sensory decisions are made under several simultaneous behavioral demands.

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bioRxiv2021

Cortical efficient coding dynamics shape behavioral performance.

Neurons throughout the sensory pathway adapt their responses depending on the statistical structure of the sensory environment. Contrast gain control is a form of adaptation in the auditory cortex, but it is unclear whether the dynamics of gain control reflect efficient adaptation, and whether they shape behavioral perception. Here, we trained mice to detect a target presented in background noise shortly after a change in the contrast of the background. The observed changes in cortical gain and behavioral detection followed the dynamics of a normative model of efficient contrast gain control; specifically, target detection and sensitivity improved slowly in low contrast, but degraded rapidly in high contrast. Auditory cortex was required for this task, and cortical responses were not only similarly affected by contrast but predicted variability in behavioral performance. Combined, our results demonstrate that dynamic gain adaptation supports efficient coding in auditory cortex and predicts the perception of sounds in noise.

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bioRxiv2021

Sound improves neuronal encoding of visual stimuli in mouse primary visual cortex

In everyday life, we integrate visual and auditory information in routine tasks such as navigation and communication. Whereas concurrent sound can improve visual perception, the neuronal correlates of this audiovisual integration are not fully understood. Specifically, it remains unclear whether neuronal firing patters in the primary visual cortex (V1) of awake animals demonstrate similar sound-induced improvement in visual discriminability. Furthermore, presentation of sound is associated with movement in the subjects, but little is understood about whether and how sound-associated movement affects audiovisual integration in V1. We investigated how sound and movement interact to modulate V1 visual responses in awake, head-fixed mice and whether this interaction improves neuronal encoding of the visual stimulus. We presented visual drifting gratings with and without simultaneous auditory white noise to awake male and female mice while recording mouse movement and V1 neuronal activity. Sound modulated light-evoked activity of 80% of light-responsive neurons, with 95% of neurons increasing activity when the auditory stimulus was present. Sound consistently enhanced movement, however, a generalized linear model revealed that sound and movement had distinct and complementary effects of the neuronal visual responses. Furthermore, decoding of the visual stimulus from the neuronal activity was improved with sound, even when controlling for movement. Thus, sound and movement modulate visual responses in complementary ways, improving neuronal representation of the visual stimulus. This study clarifies the role of movement as a potential confound in neuronal audiovisual responses and expands our knowledge of how multimodal processing is mediated in the awake brain. Significance statementSound and movement are both known to modulate visual responses in the primary visual cortex, however sound-induced movement has largely remained unaccounted for as a potential confound in audiovisual studies in awake animals. Here, authors found that sound and movement both modulate visual responses in an important visual brain area, the primary visual cortex, in distinct, yet complementary ways. Furthermore, sound improved encoding of the visual stimulus even when accounting for movement. This study reconciles contrasting theories on the mechanism underlying audiovisual integration and asserts the primary visual cortex as a key brain region participating in tripartite sensory interactions.

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bioRxiv2021

Cortico-Fugal Regulation of Predictive Coding.

Sensory systems must account for both contextual factors and prior experience to adaptively engage with the dynamic external environment. In the central auditory system, neurons modulate their responses to sounds based on statistical context. These response modulations can be understood through a hierarchical predictive coding lens: responses to repeated stimuli are progressively decreased, in a process known as repetition suppression, whereas unexpected stimuli produce a prediction error signal. Prediction error incrementally increases along the auditory hierarchy from the inferior colliculus (IC) to the auditory cortex (AC), suggesting that these regions may engage in hierarchical predictive coding. A potential substrate for top-down predictive cues is the massive set of descending projections from the auditory cortex to subcortical structures, although the role of this system in predictive processing has never been directly assessed. We tested the effect of optogenetic inactivation of the auditory cortico-collicular feedback in awake mice on responses of IC neurons to stimuli designed to test prediction error and repetition suppression. Inactivation of the cortico-collicular pathway led to a decrease in prediction error in IC. Repetition suppression was unaffected by cortico-collicular inactivation, suggesting that this metric may reflect fatigue of bottom-up sensory inputs rather than predictive processing. We also discovered populations of IC neurons that exhibit repetition enhancement, a sequential increase in firing with stimulus repetition. Cortico-collicular inactivation led to a decrease in repetition enhancement in the central nucleus of IC, suggesting that it is a top-down phenomenon. Negative prediction error, a stronger response to a tone in a predictable rather than unpredictable sequence, was suppressed in shell IC units during cortico-collicular inactivation. These changes in predictive coding metrics arose from bidirectional modulations in the response to the standard and deviant contexts, such that neurons in IC responded more similarly to each context in the absence of cortical input. We also investigated how these metrics compare between the anesthetized and awake states by recording from the same neurons under both conditions. We found that metrics of predictive coding and deviance detection differ depending on the anesthetic state of the animal, with negative prediction error emerging in the central IC and repetition enhancement and prediction error being more prevalent in the absence of anesthesia. Overall, our results demonstrate that the auditory cortex provides cues about the statistical context of sound to subcortical brain regions via direct feedback, regulating processing of both prediction and repetition.

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bioRxiv2020

Neuronal activity in sensory cortex predicts the specificity of learning.

Learning to avoid dangerous signals while preserving normal responses to safe stimuli is essential for everyday behavior and survival. Fear learning has a high level of inter-subject variability. Following identical experiences, subjects exhibit fear specificities ranging from high (specializing fear to only the dangerous stimulus) to low (generalizing fear to safe stimuli). Pathological fear generalization underlies emotional disorders, such as post-traumatic stress disorder. The neuronal basis of fear specificity remains unknown. Here, we identified the neuronal code that underlies inter-subject variability in fear specificity using longitudinal imaging of neuronal activity before and after differential fear conditioning in the auditory cortex of mice. Neuronal activity prior to, but not after learning predicted the level of specificity following fear conditioning across subjects. Stimulus representation in auditory cortex was reorganized following conditioning. However, the reorganized neuronal activity did not relate to the specificity of learning. These results present a novel neuronal code that determines individual patterns in learning.

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bioRxiv2019

A Unifying Mechanistic Model of the Auditory Cortex with Inhibitory Subtypes

The mammalian sensory cortex is composed of multiple types of inhibitory and excitatory neurons, which form sophisticated microcircuits for processing and transmitting sensory information. Despite rapid progress in understanding the function of distinct neuronal populations, the parameters of connectivity that are required for the function of these microcircuits remain unknown. Recent studies found that two most common inhibitory interneurons, parvalbumin- (PV) and somatostatin-(SST) positive interneurons control sound-evoked responses, temporal adaptation and network dynamics in the auditory cortex (AC). These studies can inform our understanding of parameters for the connectivity of excitatory-inhibitory cortical circuits. Specifically, we asked whether a common microcircuit can account for the disparate effects found in studies by different groups. By starting with a cortical rate model, we find that a simple current-compensating mechanism accounts for the experimental findings from multiple groups. They key mechanisms are two-fold. First, PVs compensate for reduced SST activity when thalamic inputs are strong with less compensation when thalamic inputs are weak. Second, SSTs are generally disinhibited by reduced PV activity regardless of thalamic input strength. These roles are augmented by plastic synapses. These differential roles reproduce the differential effects of PVs and SSTs in stimulus-specific adaptation, forward suppression and tuning-curve adaptation, as well as the influence of PVs on feedforward functional connectivity in the circuit. This circuit exhibits a balance of inhibitory and excitatory currents that persists on stimulation. This approach brings together multiple findings from different laboratories and identifies a circuit that can be used in future studies of upstream and downstream sensory processing. Significance StatementThe mammalian auditory cortex is composed of multiple types of inhibitory and excitatory neurons, which form sophisticated microcircuits for processing and transmitting sensory information. Distinct inhibitory neuron subtypes play distinct functions in auditory processing, but it remains unknown what simple set of underlying mechanisms is responsible for inhibitory cortical function. Here, we built minimal rate and spiking models and identified a specific set of synaptic mechanisms that could best reproduce the broad set of experimental results in the auditory cortex. The simplicity of our model provides an understanding of inhibitory cortical processing at the circuit level, which explains results from different laboratories, and provides for a novel computational framework for future studies of cortical function.

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bioRxiv2019

A novel mechanism for amplification of sensory responses by the amygdala-TRN projections.

Many forms of behavior require selective amplification of neuronal representations of relevant environmental signals. Following emotional learning, sensory stimuli drive enhanced responses in the sensory cortex. However, the brain circuits that underlie emotionally driven control of the sensory representations remain poorly understood. Here we identify a novel pathway between the basolateral amygdala (BLA), an emotional learning center in the mouse brain, and the inhibitory nucleus of the thalamus (TRN). We demonstrate that activation of this pathway amplifies sound-evoked activity in the central auditory pathway. Optogenetic activation of BLA suppressed spontaneous, but not tone-evoked activity in the auditory cortex (AC), effectively amplifying tone-evoked responses in AC. Anterograde and retrograde viral tracing identified robust BLA projections terminating at TRN. Optogenetic activation of amygdala-TRN pathway mimicked the effect of direct BLA activation, amplifying tone-evoked responses in the auditory thalamus and cortex. The results are explained by a computational model of the thalamocortical circuitry. In our model, activation of TRN by BLA suppresses spontaneous activity in thalamocortical cells, and as a result, thalamocortical neurons are primed to relay relevant sensory input. These results demonstrate a novel circuit mechanism for shining a neural spotlight on behaviorally relevant signals and provide a potential target for treatment of neuropsychological disorders, in which emotional control of sensory processing is disrupted.

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bioRxiv2019

The role of feedback from the auditory cortex in shaping responses to sounds in inferior colliculus

The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports critical aspects of auditory behavior but has not been extensively characterized. Previous studies demonstrated that activity in IC is altered by focal electrical stimulation and pharmacological inactivation of AC, but these methods lack the ability to selectively manipulate projection neurons. We measured the effects of selective optogenetic modulation of cortico-collicular feedback projections on IC sound responses in mice. Activation of feedback increased spontaneous activity and decreased stimulus selectivity in IC, whereas suppression had no effect. To further understand how microcircuits in AC may control collicular activity, we optogenetically modulated different cortical neuronal subtypes, specifically parvalbumin-positive (PV) and somatostatin-positive (SST) inhibitory interneurons. We found that modulating either type of interneuron did not affect IC sound-evoked activity. Combined, our results identify that activation of excitatory projections, but not inhibition-driven changes in cortical activity, affects collicular sound responses.

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bioRxiv2017

Cortical interneurons ensure maintenance of frequency tuning following adaptation.

Neurons throughout the sensory pathway are tuned to specific aspects of stimuli. This selectivity is shaped by feedforward and recurrent excitatory-inhibitory interactions. In the auditory cortex (AC), two large classes of interneurons, parvalbumin- (PVs) and somatostatin- positive (SOMs) interneurons, differentially modulate frequency-dependent responses across the frequency response function of excitatory neurons. At the same time, the responsiveness of neurons in AC to sounds is dependent on the temporal context, with the majority of neurons exhibiting adaptation to repeated sounds. Here, we asked whether and how inhibitory neurons shape the frequency response function of excitatory neurons as a function of adaptation to temporal repetition of tones. The effects of suppressing both SOMs and PVs diverged for responses to preferred versus non-preferred frequencies following adaptation. Prior to adaptation, suppressing either SOM or PV inhibition drove both increases and decreases in spiking activity among cortical neurons. After adaptation, suppressing SOM activity caused predominantly disinhibitory effects, whereas suppressing PV activity still evoked bi-directional changes. SOM, but not PV-driven inhibition dynamically modulated frequency tuning as a function of adaptation. Additionally, testing across frequency tuning revealed that, unlike PVs, SOM-driven inhibition exhibited gain-like increases reflective of adaptation. Our findings suggest that distinct cortical interneurons differentially shape tuning to sensory stimuli across the neuronal receptive field, maintaining frequency selectivity of excitatory neurons during adaptation.

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bioRxiv2017

Cortical neural activity predicts sensory acuity under optogenetic manipulation.

Excitatory and inhibitory neurons in the mammalian sensory cortex form interconnected circuits that control cortical stimulus selectivity and sensory acuity. Theoretical studies have predicted that suppression of inhibition in such excitatory-inhibitory networks can lead to either an increase or, paradoxically, a decrease in excitatory neuronal firing, with consequent effects on stimulus selectivity. We tested whether modulation of inhibition or excitation in the auditory cortex could evoke such a variety of effects in tone-evoked responses and in behavioral frequency discrimination acuity. We found that, indeed, the effects of optogenetic manipulation on stimulus selectivity and behavior varied in both magnitude and sign across subjects, possibly reflecting differences in circuitry or expression of optogenetic factors. Changes in neural population responses consistently predicted behavioral changes for individuals separately, including improvement and impairment in acuity. This correlation between cortical and behavioral change demonstrates that, despite complex and varied effects these manipulations can have on neuronal dynamics, the resulting changes in cortical activity account for accompanying changes in behavioral acuity.\n\nAuthor summaryExcitatory and inhibitory interactions determine stimulus specificity and tuning in sensory cortex, thereby controlling perceptual discrimination acuity. Modeling of such excitatory-inhibitory circuits has predicted that suppressing the activity of inhibitory neurons can lead to increases or, paradoxically, decreases in excitatory activity, depending on the architecture and modulation parameters of the inhibitory component of the network. Here, we capitalized on differences between subjects to test whether suppressing/activating inhibition and excitation across a range of parameters in sensory cortex can in fact exhibit such paradoxical effects for both stimulus sensitivity and behavioral discriminability. Indeed, we found that the same optogenetic manipulation in the auditory cortices of different mice could improve or impair frequency discrimination acuity, in a fashion that was predictable from the effects on cortical responses to tones. The same manipulations sometimes produced opposite changes in the behavior of different individuals, supporting theoretical predictions for inhibition-stabilized networks.

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