Associate Professor, Department of Psychology
Ph.D. California Institute of Technology
Sc.B. Brown University
Research Interests: How local circuits in the auditory cortex encode and transform sensory information
Overview: We study how local circuits in the cerebral cortex encode and transform sensory information. We use the rodent auditory cortex as a model system to investigate how cellular and network properties shape cortical responses to a continuous and temporally complex stream of sensory data. Research in my laboratory combines aspects of both cellular, systems, and computational neuroscience, by using the tools of molecular biology and cellular physiology to address systems-level questions. By using a variety of electrophysiological approaches, in particular in vivo whole cell recording methods in combination with molecular manipulations, we are trying to identify the cellular and synaptic mechanisms with which cortical circuits process auditory information, leading ultimately to our perceptual experiences of acoustic streams, such as music and speech.
5XFAD Mice Show Early Onset Gap Detection Deficits.
Front Aging Neurosci. 2019;11:66
Authors: Kaylegian K, Stebritz AJ, Weible AP, Wehr M
Alzheimer's patients show auditory temporal processing deficits very early in disease progression, before the onset of major cognitive impairments. In addition to potentially contributing to speech perception and communication deficits in patients, this also represents a potential early biomarker for Alzheimer's. For this reason, tests of temporal processing such as gap detection have been proposed as an early diagnosis tool. For a biomarker such as gap detection deficits to have maximum clinical value, it is important to understand what underlying neuropathology it reflects. For example, temporal processing deficits could arise from alterations at cortical, midbrain, or brainstem levels. Mouse models of Alzheimer's disease can provide the ability to reveal in detail the molecular and circuit pathology underlying disease symptoms. Here we tested whether 5XFAD mice, a leading Alzheimer's mouse model, exhibit impaired temporal processing. We found that 5XFAD mice showed robust gap detection deficits. Gap detection deficits were first detectable at about 2 months of age and became progressively worse, especially for males and for longer gap durations. We conclude that 5XFAD mice are well-suited to serve as a model for understanding the circuit mechanisms that contribute to Alzheimer's-related gap detection deficits.
PMID: 31001105 [PubMed]
Gap encoding by parvalbumin-expressing interneurons in auditory cortex.
J Neurophysiol. 2018 07 01;120(1):105-114
Authors: Keller CH, Kaylegian K, Wehr M
Synaptic inhibition shapes the temporal processing of sounds in auditory cortex, but the contribution of specific inhibitory cell types to temporal processing remains unclear. We recorded from parvalbumin-expressing (PV+) interneurons in auditory cortex to determine how they encode gaps in noise, a model of temporal processing more generally. We found that PV+ cells had stronger and more prevalent on-responses, off-responses, and postresponse suppression compared with presumed pyramidal cells. We summarize this pattern of differences as "deeper modulation" of gap responses in PV+ cells. Response latencies were also markedly faster for PV+ cells. We found a similar pattern of deeper modulation and faster latencies for responses to white noise bursts, suggesting that these are general properties of on- and off-responses in PV+ cells rather than specific features of gap encoding. These findings are consistent with a role for PV+ cells in providing dynamic gain control by pooling local activity. NEW & NOTEWORTHY We found that parvalbumin-expressing (PV+) interneurons in auditory cortex showed more deeply modulated responses to both gaps in noise and bursts of noise, suggesting that they are optimized for the rapid detection of stimulus transients.
PMID: 29589814 [PubMed - in process]
Rapid Rebalancing of Excitation and Inhibition by Cortical Circuitry.
Neuron. 2018 Mar 21;97(6):1341-1355.e6
Authors: Moore AK, Weible AP, Balmer TS, Trussell LO, Wehr M
Excitation is balanced by inhibition to cortical neurons across a wide range of conditions. To understand how this relationship is maintained, we broadly suppressed the activity of parvalbumin-expressing (PV+) inhibitory neurons and asked how this affected the balance of excitation and inhibition throughout auditory cortex. Activating archaerhodopsin in PV+ neurons effectively suppressed them in layer 4. However, the resulting increase in excitation outweighed Arch suppression and produced a net increase in PV+ activity in downstream layers. Consequently, suppressing PV+ neurons did not reduce inhibition to principal neurons (PNs) but instead resulted in a tightly coordinated increase in both excitation and inhibition. The increase in inhibition constrained the magnitude of PN spiking responses to the increase in excitation and produced nonlinear changes in spike tuning. Excitatory-inhibitory rebalancing is mediated by strong PN-PV+ connectivity within and between layers and is likely engaged during normal cortical operation to ensure balance in downstream neurons.
PMID: 29503186 [PubMed - in process]
Vision Drives Accurate Approach Behavior during Prey Capture in Laboratory Mice.
Curr Biol. 2016 11 21;26(22):3046-3052
Authors: Hoy JL, Yavorska I, Wehr M, Niell CM
The ability to genetically identify and manipulate neural circuits in the mouse is rapidly advancing our understanding of visual processing in the mammalian brain [1, 2]. However, studies investigating the circuitry that underlies complex ethologically relevant visual behaviors in the mouse have been primarily restricted to fear responses [3-5]. Here, we show that a laboratory strain of mouse (Mus musculus, C57BL/6J) robustly pursues, captures, and consumes live insect prey and that vision is necessary for mice to perform the accurate orienting and approach behaviors leading to capture. Specifically, we differentially perturbed visual or auditory input in mice and determined that visual input is required for accurate approach, allowing maintenance of bearing to within 11° of the target on average during pursuit. While mice were able to capture prey without vision, the accuracy of their approaches and capture rate dramatically declined. To better explore the contribution of vision to this behavior, we developed a simple assay that isolated visual cues and simplified analysis of the visually guided approach. Together, our results demonstrate that laboratory mice are capable of exhibiting dynamic and accurate visually guided approach behaviors and provide a means to estimate the visual features that drive behavior within an ethological context.
PMID: 27773567 [PubMed - indexed for MEDLINE]
Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits.
Front Neural Circuits. 2016;10:76
Authors: Yavorska I, Wehr M
Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM) inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons.
PMID: 27746722 [PubMed - indexed for MEDLINE]
A coding transformation for temporally structured sounds within auditory cortical neurons.
Neuron. 2015 Apr 08;86(1):292-303
Authors: Gao X, Wehr M
Although the coding transformation between visual thalamus and cortex has been known for over 50 years, whether a similar transformation occurs between auditory thalamus and cortex has remained elusive. Such a transformation may occur for time-varying sounds, such as music or speech. Most subcortical neurons explicitly encode the temporal structure of sounds with the temporal structure of their activity, but many auditory cortical neurons instead use a rate code. The mechanisms for this transformation from temporal code to rate code have remained unknown. Here we report that the membrane potential of rat auditory cortical neurons can show stimulus synchronization to rates up to 500 Hz, even when the spiking output does not. Synaptic inputs to rate-coding neurons arose in part from temporal-coding neurons but were transformed by voltage-dependent properties and push-pull excitatory-inhibitory interactions. This suggests that the transformation from temporal to rate code can be observed within individual cortical neurons.
PMID: 25819614 [PubMed - indexed for MEDLINE]
A guide to in vivo single-unit recording from optogenetically identified cortical inhibitory interneurons.
J Vis Exp. 2014 Nov 07;(93):e51757
Authors: Moore AK, Wehr M
A major challenge in neurophysiology has been to characterize the response properties and function of the numerous inhibitory cell types in the cerebral cortex. We here share our strategy for obtaining stable, well-isolated single-unit recordings from identified inhibitory interneurons in the anesthetized mouse cortex using a method developed by Lima and colleagues. Recordings are performed in mice expressing Channelrhodopsin-2 (ChR2) in specific neuronal subpopulations. Members of the population are identified by their response to a brief flash of blue light. This technique - termed "PINP", or Photostimulation-assisted Identification of Neuronal Populations - can be implemented with standard extracellular recording equipment. It can serve as an inexpensive and accessible alternative to calcium imaging or visually-guided patching, for the purpose of targeting extracellular recordings to genetically-identified cells. Here we provide a set of guidelines for optimizing the method in everyday practice. We refined our strategy specifically for targeting parvalbumin-positive (PV+) cells, but have found that it works for other interneuron types as well, such as somatostatin-expressing (SOM+) and calretinin-expressing (CR+) interneurons.
PMID: 25407742 [PubMed - indexed for MEDLINE]
Auditory cortex is required for fear potentiation of gap detection.
J Neurosci. 2014 Nov 12;34(46):15437-45
Authors: Weible AP, Liu C, Niell CM, Wehr M
Auditory cortex is necessary for the perceptual detection of brief gaps in noise, but is not necessary for many other auditory tasks such as frequency discrimination, prepulse inhibition of startle responses, or fear conditioning with pure tones. It remains unclear why auditory cortex should be necessary for some auditory tasks but not others. One possibility is that auditory cortex is causally involved in gap detection and other forms of temporal processing in order to associate meaning with temporally structured sounds. This predicts that auditory cortex should be necessary for associating meaning with gaps. To test this prediction, we developed a fear conditioning paradigm for mice based on gap detection. We found that pairing a 10 or 100 ms gap with an aversive stimulus caused a robust enhancement of gap detection measured 6 h later, which we refer to as fear potentiation of gap detection. Optogenetic suppression of auditory cortex during pairing abolished this fear potentiation, indicating that auditory cortex is critically involved in associating temporally structured sounds with emotionally salient events.
PMID: 25392510 [PubMed - indexed for MEDLINE]