Biology subjects

Zak, J. D.

Publications and source records attributed to Zak, J. D..

11 recordsLinked to original sources

bioRxiv2025

Neuroinflammation in Olfactory Circuits Underlies Odor Hypersensitivity in a Rodent Model of Depression

Olfactory anhedonia and heightened aversion to unpleasant odors are well-documented features of depression in humans, yet the neural mechanisms linking chronic stress to altered olfactory perception remain poorly understood. We used the Unpredictable Chronic Mild Stress (UCMS) paradigm to examine how chronic stress affects olfactory avoidance behavior and glial cell morphology across multiple olfactory brain regions in male and female mice. UCMS-treated mice showed increased avoidance of aversive odorants in an odorized light/dark box assay, consistent with heightened aversive reactivity to odors following chronic stress. Using immunohistochemistry, we assessed microglial morphology and astrocyte density across six olfactory and limbic brain regions. Chronic stress produced region-specific glial remodeling: astrocyte counts were selectively elevated in the medial amygdala, and microglial process complexity was increased in the anterior olfactory nucleus and anterior piriform cortex. Microglial morphological complexity in the anterior piriform cortex was correlated with individual odor avoidance scores. These findings reveal that chronic stress induces regionally specific glial plasticity within olfactory sensory and affective networks and suggest that microglial remodeling in piriform cortex may contribute to stress-related changes in olfactory perception. Significance StatementChanges in sensory perception frequently accompany depression. While previous studies have implicated neuroinflammation in depression-related dysfunction within cortical and limbic structures, little is known about how chronic stress affects glial cells in olfactory processing regions. Here, we show that chronic stress induces glial remodeling in key olfactory areas, including the olfactory bulb, anterior piriform cortex, and medial amygdala, and that these changes correlate with heightened behavioral avoidance of aversive odors. These findings suggest that glial plasticity in sensory networks contributes to affective alterations in olfactory perception, revealing a potential mechanism by which mood disorders can influence sensory experience. This work advances our understanding of the neuroimmune basis of sensory-affective integration.

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bioRxiv2025

Perception and neural representation of intermittent odor stimuli in mice

Odor cues in nature are sparse and highly fluctuating due to turbulent transport. To investigate how animals perceive these intermittent cues, we developed a behavioral task in which head-restrained mice made binary decisions based on the total number of discrete odor pulses presented stochastically over several seconds. Mice readily learned this task, and their performance was well-described by widely used decision models. Logistic regression of binary choices against the timing of odor pulses within the respiratory cycle revealed that mice placed higher perceptual weight to stimuli arriving during inhalation than exhalation, a phase dependency that strongly correlated with the magnitude of responses in olfactory sensory neurons. The population response of anterior piriform cortex (APCx) neurons to odor pulses was also modulated by respiration phase, although individual neurons displayed varying levels of phase-dependence. Single APCx neurons responded stochastically and transiently to odor pulses, leading to a representation that carries signatures of sensory evidence, but not its accumulation. Our study reveals that mice can integrate intermittent odor signals across dozens of breaths, but respiratory modulation of sensory inputs imposes limits on information acquisition that cortical circuits cannot overcome to improve behavior.

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bioRxiv2024

Amplification of olfactory transduction currents implements sparse stimulus encoding

Sensory systems must perform the dual and opposing tasks of being sensitive to weak stimuli while also maintaining information content in dense and variable sensory landscapes. This occurs in the olfactory system, where OSNs are highly sensitive to low concentrations of odors and maintain discriminability in complex odor environments. How olfactory sensory neurons (OSNs) maintain both sensitivity and sparsity is not well understood. Here, we investigated whether the calcium-activated chloride channel, TMEM16B, may support these dual roles in OSNs. We used multiphoton microscopy to image the stimulus-response density of OSNs in the olfactory epithelium. In TMEM16B knockout mice, we found that sensory representations were denser, and the magnitude of OSN responses was increased. Behaviorally, these changes in sensory representations were associated with an increased aversion to the odorant trimethylamine, which switches perceptual valence as its concentration increases, and a decreased efficiency of olfactory-guided navigation. Together, our results indicate that the calcium-activated chloride channel TMEM16B sparsens sensory representations in the peripheral olfactory system and contributes to efficient integrative olfactory-guided behaviors.

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bioRxiv2024

Reduction of Neuroinflammation and Seizures in a Mouse Model of CLN1 Batten Disease using the Small Molecule Enzyme Mimetic, N-Tert-Butyl Hydroxylamine.

Infantile neuronal ceroid lipofuscinosis (CLN1 Batten Disease) is a devastating pediatric lysosomal storage disease caused by pathogenic variants in the CLN1 gene, which encodes the depalmitoylation enzyme, palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients present with visual deterioration, psychomotor dysfunction, and recurrent seizures until neurodegeneration results in death, typically before fifteen years of age. Histopathological features of CLN1 include aggregation of lysosomal autofluorescent storage material (AFSM), as well as profound gliosis. The current management of CLN1 is relegated to palliative care. Here, we examine the therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine (NtBuHA), in a Cln1-/- mouse model. Treatment with NtBuHA reduced AFSM accumulation both in vitro and in vivo. Importantly, NtBuHA treatment in Cln1-/- mice reduced neuroinflammation, mitigated epileptic episodes, and normalized motor function. Live cell imaging of Cln1-/- primary cortical neurons treated with NtBuHA partially rescued aberrant synaptic calcium dynamics, suggesting a potential mechanism contributing to the therapeutic effects of NtBuHA in vivo. Taken together, our findings provide supporting evidence for NtBuHA as a potential treatment for CLN1 Batten Disease.

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bioRxiv2023

Distinct information conveyed to the olfactory bulb by feedforward input from the nose and feedback from the cortex

Sensory systems are organized hierarchically, but feedback projections frequently disrupt this order. In the olfactory bulb (OB), cortical feedback projections numerically match sensory inputs. To unravel information carried by these two streams, we imaged the activity of olfactory sensory neurons (OSNs) and cortical axons in the mouse OB using calcium indicators, multiphoton microscopy, and diverse olfactory stimuli. Odorant mixtures of increasing complexity evoked progressively denser OSN activity, yet cortical feedback activity was of similar sparsity for all stimuli. Representations of complex mixtures were similar in OSNs but were decorrelated in cortical axons. While OSN responses to increasing odorant concentrations exhibited a sigmoidal relationship, cortical axonal responses were complex and non-monotonic, which could be explained by a model with activity-dependent feedback inhibition in the cortex. Our study indicates that early-stage olfactory circuits have access to both local feedforward signals and global, efficiently formatted information about odor scenes through cortical feedback.

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bioRxiv2023

Neural circuits for fast Poisson compressed sensing in the olfactory bulb

Within a single sniff, the mammalian olfactory system can decode the identity and concentration of odorants wafted on turbulent plumes of air. Yet, it must do so given access only to the noisy, dimensionally-reduced representation of the odor world provided by olfactory receptor neurons. As a result, the olfactory system must solve a compressed sensing problem, relying on the fact that only a handful of the millions of possible odorants are present in a given scene. Inspired by this principle, past works have proposed normative compressed sensing models for olfactory decoding. However, these models have not captured the unique anatomy and physiology of the olfactory bulb, nor have they shown that sensing can be achieved within the 100-millisecond timescale of a single sniff. Here, we propose a rate-based Poisson compressed sensing circuit model for the olfactory bulb. This model maps onto the neuron classes of the olfactory bulb, and recapitulates salient features of their connectivity and physiology. For circuit sizes comparable to the human olfactory bulb, we show that this model can accurately detect tens of odors within the timescale of a single sniff. We also show that this model can perform Bayesian posterior sampling for accurate uncertainty estimation. Fast inference is possible only if the geometry of the neural code is chosen to match receptor properties, yielding a distributed neural code that is not axis-aligned to individual odor identities. Our results illustrate how normative modeling can help us map function onto specific neural circuits to generate new hypotheses.

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bioRxiv2021

Neurotransmitter regulation rather than cell-intrinsic properties shape the high-pass filtering properties of olfactory bulb glomeruli

GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate an intraglomerular "high-pass" filter through inhibition targeted onto a glomerulus. With this mechanism, weak stimuli (e.g., an odor with a low affinity for an odorant receptor) mainly produce PG cell-driven inhibition but strong stimuli generate enough excitation to overcome inhibition. PG cells may be particularly susceptible to being activated by weak stimuli due to their intrinsically small size and high input resistance. Here, we used dual-cell patch-clamp recordings and imaging methods in bulb slices obtained from wild-type and transgenic rats with labeled GABAergic cells to test a number of predictions of the high-pass filtering model. We first directly compared the responsiveness of PG cells with that of external tufted cells (eTCs), which are a class of excitatory interneurons that reside in a parallel but opposing position in the glomerular circuitry. PG cells were in fact found to be no more responsive than eTCs at low levels of sensory neuron activity. While PG cells required smaller currents to be excited, this advantage was offset by the fact that a given level of sensory neuron activity produced much smaller synaptic currents. We did however identify other factors that shaped the excitation/inhibition balance in a manner that would support a high-pass filter, including glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high-pass filter to enhance the contrast between different olfactory stimuli through mechanisms that are largely independent cell intrinsic properties. Key Points SummaryO_LIGABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate a "high-pass" filter at a single glomerulus that selectively blocks weak stimulus signals. Their efficacy may reflect their intrinsically small size and high input resistance, which allows them to be easily excited. C_LIO_LIWe found that PG cells were in fact no more likely to be activated by weak stimuli than excitatory neurons. PG cells spiked more readily in response to a fixed current input, but this advantage for excitability was offset by small synaptic currents. C_LIO_LIGlomeruli nevertheless display an excitation/inhibition balance that can support a high pass filter, becoming much more favorable with increasing stimulus strength. Factors shaping the filter include glial glutamate transporters and presynaptic metabotropic glutamate receptors. C_LIO_LIWe conclude that a single glomerulus may act as a high-pass filter to enhance stimulus contrast through mechanisms that are largely independent of cell-intrinsic properties. C_LI

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bioRxiv2021

Optical manipulations reveal strong reciprocal inhibition but limited recurrent excitation within olfactory bulb glomeruli

The local circuitry within olfactory bulb glomeruli filters, transforms, and facilitates information transfer from olfactory sensory neurons to bulb output neurons. Two key elements of this circuit are glutamatergic tufted cells (TCs) and GABAergic periglomerular (PG) cells, both of which actively shape mitral cell activity and bulb output. A subtype of TCs, the external tufted cells (eTCs), can synaptically excite PG cells, but there are unresolved questions about other aspects of the glomerular connections, including the extent of connectivity between eTCs and the precise nature of reciprocal interactions between eTCs and PG cells. We combined patch-clamp recordings in OB slices and optophysiological tools to investigate local functional connections within glomeruli. When TCs were optically suppressed, we found a large decrease in excitatory post-synaptic currents (EPSCs) in "uniglomerular" PG cells that extend dendrites to one glomerulus, indicating that TC activation was required for most excitation of these PG cells. However, TC suppression had no effect on EPSCs in eTCs, arguing that TCs make few, if any, direct excitatory synaptic connections onto eTCs. The absence of synaptic connections between eTCs was also supported by recordings in eTC pairs. Lastly, we show using similar optical suppression methods that PG cells that express GAD65, mainly uniglomerular PG cells, provide strong inhibition onto eTCs. Our results indicate that the local network of TCs form potent reciprocal synaptic connections with GAD65-expressing uniglomerular PG cells but not other TCs. This configuration favors local inhibition over recurrent excitation within a glomerulus, limiting information transfer to downstream cortical regions.

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bioRxiv2019

Antagonistic odor interactions in olfactory sensory neurons are widespread in freely breathing mice

Odor landscapes contain complex blends of discrete molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we found widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions became stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a remarkably common feature of odor mixture encoding in olfactory sensory neurons and helps in normalizing activity to reduce saturation.

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bioRxiv2018

Thresholding of sensory inputs by extrasynaptic glutamate receptors in olfactory bulb glomeruli

The mammalian olfactory bulb has presented a challenging system for understanding information processing, in part because the bulb largely lacks the topographical ordering of neurons that promotes processes such as lateral inhibition. Here we have used dual and triple-cell recordings in rodent bulb slices combined with ultrastructural methods to provide the first experimental evidence for a processing mechanism circumventing this problem that operates at the level of single glomeruli, the bulbs odorant receptor-specific modules. A key feature is non-traditional, extrasynaptic glutamatergic signaling derived from excitatory interneurons and what it means for the local balance between excitation (E) and inhibition (I). We found that the distinct dynamic properties of extrasynaptic excitation versus synaptic inhibition create a thresholding effect whereby only strong stimuli produce a favorable E/I balance enabling an output. This single-glomerulus threshold could have a number of important functions during natural odor responses, for example enhancing stimulus tuning.

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bioRxiv2018

Calcium-activated chloride channels clamp odor-evoked spike activity in olfactory receptor neurons

The calcium-activated chloride channel anoctamin-2 (Ano2) is thought to amplify transduction currents in ORNs, a hypothesis supported by previous studies in dissociated neurons from Ano2-/- mice. Paradoxically, despite a reduction in transduction currents in Ano2-/- ORNs, their spike output for odor stimuli may be higher. We examined the role of Ano2 in ORNs in their native environment in freely breathing mice by imaging activity in ORN axons as they arrive in the olfactory bulb glomeruli. Odor-evoked responses in ORN axons of Ano2-/- mice were consistently larger for a variety of odorants and concentrations. In an open arena, Ano2-/- mice took longer to approach a localized odor source than wild-type mice, revealing clear olfactory behavioral deficits. Our studies provide the first in vivo evidence toward an alternative role for Ano2 in the olfactory transduction cascade, where it may serve as a feedback mechanism to clamp ORN spike output.

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