Research

The nervous system processes information about the environment, sets internal states, and respond with motor output patterns. Many neural processing tasks share remarkable abilities to identify multiple “objects” in a sensory field, to track objects through time, and to utilize sensory cues that are at or close to the physical limits of detection or discriminability.

In our laboratory, we study the cellular mechanisms used by neurons in the auditory system to try to understand how this processing takes place. Our approach is broad, and includes three kinds of studies: ion channels and electrical excitability, synaptic transmission and synaptic plasticity, and computational modeling.

Our early work led to the identification of specific patterns of expression of ion channels that support the very rapid temporal processing capabilities needed for tasks such as sound localization and decoding of communication sounds - including speech [1]. We also have found patterns of expression of neurotransmitter receptors, proteins in neurons that respond to chemicals released by other neurons by opening ion channels, that support other aspects of sensory processing [2].

For the past several years, we have been studying the organization of the neural networks that support sensory and other nueral information processing. The specific patterns of connections between cells, sometimes now termed “connectomics”, structure the way that information is processed. These connections are also affected by environmental insults, such as hearing loss, and by genetics, including those that contribute to psychiatric and neurological diseases. Our tools and approaches to study these networks are allowing us to look at specific parts of neural circuits and ask how they are modified by changes in the expression of specific genes or by the environment. Ongoing experiments are examining networks in the cochlear nucleus [3] and in the primary auditory cortex. Other experiments are testing ideas about functional inhibitory networks in the prefrontal cortex. These experiments use optical tools, primaily in conjunction with laser scanning photostimulation, and include glutamate uncaging and targeted optogenetics with channelrhodopsin expression in selected subsets of in transgenic mice.

Finally, while experimental science is the basis for gaining insight into function and mechanism, the way that the nervous system operates is complex and non-linear. To help us understand neural information processing, we use computational models, which may be viewed as formal (mathematical) statements of hypotheses. These models allow us to test ideas and generate predictions that are not always intuitively evident. Models do not substitute for experiments, but they can suggest experiments (prediction), or they can confirm the consistency of experimental results with prior assumptions (postdiction). By combining models with experiments, we gain greater insight into neural processes, and are forced to examine our assumptions more closely. I have often been surprised by the insights that the process of developing models has provided, and the importance of an interplay between the model development and ongoing experiments. We discover that there are critical bits of knowledge that we need to know (measure) in order to test hypotheses, and we discover the limitations of those hypotheses.

Why the auditory system? First, from the standpoint of trying to understand how the nervous system process information, the auditory system seems to offer some advantages. Hearing involves the excitation of a set of sensory receptors (hair cells) that are linearly organized on the sensory epithelium in such a way that each receptor responds to a particular range of frequencies. Each hair cell then connects to between 10 and 30 auditory nerve fibers that transmit information about a particular frequency segment to the brain. While cochlear transduction - the conversion of sound to electrical signals - is not fully understood on a molecular level, models now exist that do a very good job of replicating the information present in the auditory nerve fibers. In a simplified version, we can view the cochlea as a frequency analyzer, and this one-dimensional representation seems to reduce the complexity of the analysis that must occur centrally.

A second reason is that hearing is an important sense for communication. We use spoken language to communicate, and animals have a variety of species-specific vocalizations that are used to communicate basic information - warnings about predators, individual identification, advertising for mating - amongst members of a social group. In humans, the loss of hearing, particularly in the elderly, leads to social isolation and may be an important factor that contributes to cognitive decline. The loss of hearing can also lead to phantom perception of sounds, called “tinnitus”, a phenomenon that we now recognize as a complex central state that may involve the reorganization of synaptic connections, ion channels, and affective pathways.

Our understanding of how the nervous system works has grown tremendously over the past 150 years. However, we still have a very limited framework in which to understand the system works, and what goes wrong with environmental insults (such as hearing loss), or with aberrant development. Our long-term goal is to contribute new knowledge in these areas, using contemporary tools, carefully applied.

References:

1. Manis, P.B., Marx, S.O. Outward currents in isolated ventral cochlear nucleus neurons. J Neurosci. 1991 Sep;11(9):2865-80. Free full text at the Journal of Neuroscience

   Rothman JS, Young ED, Manis PB. Convergence of auditory nerve fibers onto bushy cells in the ventral cochlear nucleus: implications of a computational model. J Neurophysiol. 1993 Dec;70(6):2562-83. PubMed PMID: 8120599. Free full text at the Journal of Neurophysiology

   Rothman JS, Manis PB. The roles potassium currents play in regulating the electrical activity of ventral cochlear nucleus neurons. J Neurophysiol. 2003 Jun;89(6):3097-113. PubMed PMID: 12783953. Free full text at the Journal of Neurophysiology

   Rothman JS, Manis PB. Kinetic analyses of three distinct potassium conductances in ventral cochlear nucleus neurons. J Neurophysiol. 2003 Jun;89(6):3083-96. PubMed PMID: 12783952. Free full text at the Journal of Neurophysiology

   Rothman JS, Manis PB. Differential expression of three distinct potassium currents in the ventral cochlear nucleus. Neurophysiol. 2003 Jun;89(6):3070-82. PubMed PMID: 12783951. Free full text at the Journal of Neurophysiology

2. Xie R, Manis PB. Target-specific IPSC kinetics promote temporal processing in auditory parallel pathways. J Neurosci. 2013 Jan 23;33(4):1598-614. doi: 10.1523/JNEUROSCI.2541-12.2013. PubMed PMID: 23345233. Free full text at the Journal of Neuroscience

3. Campagnola L, Manis PB. A Map of Functional Synaptic Connectivity in the Mouse Anteroventral Cochlear Nucleus. J. Neurosci. 34: 2214-30, 2014. [PMID: 24501361] [PMCID: PMC3913869]