Katrina M. MacLeod - US grants

Short-term synaptic plasticity has a profound effect on the function of the neural circuit in which it is embedded. Previous work in the Nelson lab has characterized the short-term plasticity in the rat visual cortex using a quantitative (parametric) method, using trains of evoked stimuli delivered over a range of physiological frequencies. extend results previously obtained for pyramidal cells to a characterization of the short-term plasticity of inhibitory inputs to inhibitory interneurons by making whole-cell voltage-clamp recordings of nonpyramidal neurons in layers 2/3 in slices of rat neocortex. These inhibitory interneurons will be characterized and identified physiologically and morphologically. Our goals are: 1) Characterize the interneuron-interneuron synaptic plasticity of evoked IPSCs by extracellular or intracellular presynaptic stimulation; 2) Determine if the synaptic plasticity is differentially expressed depending on the interneuron subtype of the presynaptic or postsynaptic neuron; and 3) Investigate whether the interneuron-interneuron synaptic plasticity can be modified by neuro-modulatory agents such as acetylcholine. By investigating the cholinergic modulation of cortical synaptic plasticity, these results may have implications for behavioral and cognitive brain function, and the neurological disorders, such as Alzheimer's disease, which may be related cholinergic dysfunction.

Short-term synaptic plasticity has a profound effect on the function of the neural circuit in which it is embedded. Previous work in the Nelson lab has characterized the short-term plasticity in the rat visual cortex using a quantitative (parametric) method, using trains of evoked stimuli delivered over a range of physiological frequencies. extend results previously obtained for pyramidal cells to a characterization of the short-term plasticity of inhibitory inputs to inhibitory interneurons by making whole-cell voltage-clamp recordings of nonpyramidal neurons in layers 2/3 in slices of rat neocortex. These inhibitory interneurons will be characterized and identified physiologically and morphologically. Our goals are: 1) Characterize the interneuron-interneuron synaptic plasticity of evoked IPSCs by extracellular or intracellular presynaptic stimulation; 2) Determine if the synaptic plasticity is differentially expressed depending on the interneuron subtype of the presynaptic or postsynaptic neuron; and 3) Investigate whether the interneuron-interneuron synaptic plasticity can be modified by neuro-modulatory agents such as acetylcholine. By investigating the cholinergic modulation of cortical synaptic plasticity, these results may have implications for behavioral and cognitive brain function, and the neurological disorders, such as Alzheimer's disease, which may be related cholinergic dysfunction.

Dynamic changes in synaptic amplitude over short time periods, known as short-term synaptic plasticity, may have profound effects on the transmission of information between neurons. Our recent results on the short-term synaptic plasticity properties in the avian cochlear nucleus angularis (NA) demonstrated a remarkable ability to transmit information at firing frequencies that cause severe depression at other excitatory synapses in the brain. Furthermore, the depressing and facilitating plasticity components appear to be tuned such that these synapses will transmit rate information linearly, which may be critical for the encoding of acoustic intensity information. We will take advantage of an established in vitro model for cellular studies of auditory function, the brainstem slice preparation from young chickens. Using intracellular electrophysiological recordings and computational modeling, we will investigate the mechanisms responsible for the short-term plasticity at the nerve to NA synapse. We will determine whether variations in the short-term synaptic plasticity expressed in different NA neurons might contribute to distinct processing streams within the auditory brainstem. We will investigate the implications of this short-term plasticity for auditory coding by stimulating with dynamic stimuli such as simulated amplitude-modulation signals. Finally, by using the dynamic clamp methods, we will investigate how synaptic inputs, and their dynamic modulation, combine with NA neuronal intrinsic properties to generate the action potential output. These experiments are critical to our understanding of intensity processing for localization and non-localization tasks, and offer an excellent opportunity to study the implications of short-term synaptic dynamics for sensory processing. This work also has broader implications for the development of improved cochlear implant devices to recover hearing in hearing-impaired people. The cochlear nucleus is the first receiving station in the central nervous system for auditory information. While our research is focused on basic properties, a better understanding of how sound information is transformed at the auditory nerve to cochlear nucleus connection will help guide the design of cochlear implants that can stimulate more efficient, enriched sound inputs, enhancing the quality of life for the hearing-impaired.

DESCRIPTION (provided by applicant): A detailed understanding of the neurophysiological basis of hearing is fundamental to the understanding of human hearing impairment and the guidance of further development of the most successful prosthetic intervention to date, the cochlear implant. Yet we still lack a complete description of how sound information is processed at even the first central nervous system relay, the cochlear nucleus. Different aspects of sound are extracted from the auditory nerve spike trains and encoded via parallel neural pathways. While the coding of timing cues have been studied extensively, the processing of intensity cues remains unclear, especially relating to non-localization tasks such as sound recognition. We recently determined that the timing and intensity circuits in the cochlear nucleus are distinguished by the expression of different forms of short-term synaptic plasticity. In vitro studies have demonstrated that the intensity pathways exhibit a mixture of short-term facilitation and depression that allows the transmission of rate-encoded intensity information. In contrast, the short-term depression found in timing circuits creates a synaptic gain control that contributes to intensity-invariant coding of timing cues. We expand our investigation of intensity coding to spike trains in response to dynamic, amplitude modulated sounds, an important component of sound communication signals. The goal of this proposal is to identify the synaptic and cellular mechanisms that contribute to the encoding of sound intensity and establish their importance in the intact brain. Aim 1 uses the avian (chick) cochlear nucleus slice preparation to investigate two synaptic enhancement mechanisms: short-term synaptic facilitation and the contribution of NMDA-receptor currents to synaptic integration. We use dynamic clamp to determine the input-output function of cochlear nucleus neurons. Aim 2 investigates how dynamic stimuli like amplitude-modulated sounds are processed at auditory nerve synapses in the cochlear nucleus by measuring physiological synaptic responses to rate-modulated spike train inputs, using electrical stimulation and dynamic clamp. In Aim 3, we will extend our in vitro short-term plasticity results to the intact cochlear nucleus with in vivo, intracellular recordings in the avian brainstem. Given the recent advances in the restoration of hearing using prosthetic devices that stimulate the auditory nerve, it is critical to understand how nerve activity is interpreted by the central nervous system. This proposal will provide new information on the transformation of auditory information which will help improve assisted-hearing devices and lead to a better understanding of normal hearing. PUBLIC HEALTH RELEVANCE: Improved cochlear implant devices are a major goal of hearing research. Our experiments will further this goal by defining how electrical stimulation of the auditory nerve translates into physiological activity in the brainstem target, the cochlear nucleus. Examination of how modulations of sound intensity are coded by the brain will also provide new insight into the difficulties that the hearing impaired and cochlear implant patients have in understanding speech in noisy environments.