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 the Wehr lab 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.
Projects
Synaptic mechanisms of sound processing in awake rats.
Silencing of activity in genetically specified cell types.
Disruption of balanced excitation and inhibition after hearing loss.
Level dependence of contextual modulation in auditory cortex.
Synaptic mechanisms of sound processing in awake rodents.
How does synaptic processing in auditory cortex transform the neural representation of temporally structured sounds such as music and speech? Auditory cortical neurons can show distinct neural codes in awake animals that aren’t seen under anesthesia, such as sustained firing responses to long sounds, and rate-coded responses to temporally structured sounds. We are investigating the synaptic processing underlying these responses by recording from auditory cortical neurons in unanesthetized rats and mice, using in vivo whole-cell methods.
Silencing of activity in genetically specified cell types.
Most systems neuroscience is correlative. In order to establish causal relationships between neuronal activity, cortical function, and behavior, we must be able to manipulate the activity of specific types of neurons. In collaboration with the Kentros lab and the Neill lab, we are using new optogenetic and pharmocogenetic techniques to silence neurons under the control of cell-type specific promoters. With these silencing tools we are investigating the contributions of different interneuron types to different functional forms of synaptic inhibition in auditory cortical function. By combining optogenetics with new tools for imaging neuronal activity and tracing cortical microcircuitry, we can record from and manipulate connected neurons, allowing us to explore cortical circuits in unprecedented detail.
Characterizing inhibitory interneurons in auditory cortex.
In auditory cortex, sounds are encoded by neurons tuned to specific acoustic features. The sound-evoked response properties of these cells are powerfully shaped by the relative strength and timing of excitatory and inhibitory synaptic input. There are many different kinds of inhibitory neurons in the cerebral cortex, but almost nothing is known about their specific computational functions. We are using an optogenetic trick called PINPing to record from specific, genetically identified types of inhibitory interneurons. We find that the tuning and input-ouput functions of interneuron classes differ from each other and from excitatory neurons in interesting ways that provide clues about their computational function. For example, the way that Parvalbumin-expressing inhibitory neurons respond to sound frequency and intensity suggest that they play an important role in inhibitory gain control in auditory cortex.Synaptic computation for where a sound is coming from.
We often hear something important in the environment before we see, smell, or touch it. Because sound localization is so critical for survival, the auditory system has evolved sophisticated processing machinery for it, which has been very well characterized in the brainstem and midbrain. Cortical neurons are also selective for sound localization cues like ILD (Interaural Level Difference), but this selectivity has been widely assumed to be simply inherited from the subcortical structures in which the actual computation takes place. Surprisingly, we find that an inhibitory circuit computes a specific selectivity for sound localization cues in auditory cortex. Using in vivo whole-cell recordings, we find that non-preferred ILDs evoke synaptic inhibition that precedes excitation in time, as well as overpowering it in magnitude, which quenches the spiking responses for non-preferred stimuli. This means that ILD selectivity is re-computed by synaptic interactions in auditory cortex.Disruption of balanced excitation and inhibition after hearing loss.
Hearing loss disrupts the receptive fields of cortical neurons, but the synaptic mechanisms underlying these changes remain unknown. We used in vivo whole cell recordings to demonstrate that changes in the balance of excitation and inhibition play a key role. These mechanisms may be involved in the generation the phantom ringing in the ears known as tinnitus. More details on this project can be found in Scholl & Wehr 2008.Level dependence of contextual modulation in auditory cortex.
Responses of cortical neurons to sensory stimuli within their receptive fields can be profoundly altered by the stimulus context. In visual and somatosensory cortex, contextual interactions have been shown to change sign from facilitation to suppression depending on stimulus strength. We discovered that in auditory cortex, in contrast, contextual interactions were primarily suppressive across all probe levels. This suggests that context has fundamentally different effects in auditory cortex than it does in visual or somatosensory cortex. More details on this project can be found in Scholl, Gao & Wehr 2008.
Autistic individuals have a range of perceptual processing deficits, including a striking hypersensitivity to auditory stimuli. A disruption in the balance of excitation and inhibition in cortical circuits has been proposed as a model for autism and autism spectrum disorders. We are testing this hypothesis in transgenic mice generated by our collaborators Jennifer Hoy and Phil Washbourne.
