Behavior is determined not only by stimuli but also by internal states of those behavior generating networks that function as sensory motor-integrators. An important type of network state is an experience-dependent state that relies on the memory of recent experiences. Consequently, to generate responses, networks integrate both current stimuli and memories of recent experiences that are expressed as network states. We propose to study how experience dependent states are generated, expressed, and integrated with stimuli that impinge on the network. Towards this purpose, we will use a well characterized preparation that generates ingestive and egestive responses. We will use a multidisciplinary approach that combines electrophysiological, biochemical and cell-biological techniques. Repetitive stimulation of an input that elicits egestive responses establishes a network state that is manifested in repetition priming, i.e., a progressive increase of egestiveness of the response. Importantly, in the aftermath of repetitive stimulation of egestive inputs, a task switch cost is observed, i.e., stimulation of an ingestive input now elicits egestive rather than ingestive responses. The fact that the same network state has two different manifestations has made it possible to dissociate the functions of network states and network connectivity. Based on a series of recent findings, we propose that the EN- stimulation dependent network state is not implemented through recruitment of a singular set of specialized neurons but instead emerges as a result of the parallel peptidergic modulation of the excitability of several neurons that play a critical role in expressing various manifestations of network states. However, network states are not the sole determinant of responses. We propose that the specificity of responses that networks generate in different states depends not only on the momentary state of the network but also on the characteristics of neuronal connections within the network. Finally, we suggest that the mnemonic component of network states, i.e., persistent modification of neuronal excitability is mediated by peptidergic activation of specific second messenger systems whose role we propose to test. Various forms of pathology of initiation and repetition of movements are observed in Parkinsons disease, autistic children, and are also induced as a result of brain lesions. Thus, it may be hoped that understanding the mechanisms of the phenomena that we propose to study may a novel perspective on these disorders.

Public Health Relevance

We propose to study the neural basis of behavior switching and stability. These two processes are disrupted in childhood autism and Parkinson's disease. These studies may lead to novel insights into the nature of the behavioral deficits in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070583-04
Application #
8416982
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (03))
Program Officer
Gnadt, James W
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$347,607
Indirect Cost
$140,735
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Cropper, Elizabeth C; Friedman, Allyson K; Jing, Jian et al. (2014) Neuromodulation as a mechanism for the induction of repetition priming. Curr Opin Neurobiol 29:33-8
Svensson, Erik; Proekt, Alex; Jing, Jian et al. (2014) PKC-mediated GABAergic enhancement of dopaminergic responses: implication for short-term potentiation at a dual-transmitter synapse. J Neurophysiol 112:22-9
Wu, Jin-Sheng; Wang, Nan; Siniscalchi, Michael J et al. (2014) Complementary interactions between command-like interneurons that function to activate and specify motor programs. J Neurosci 34:6510-21
Dacks, Andrew M; Weiss, Klaudiusz R (2013) Latent modulation: a basis for non-disruptive promotion of two incompatible behaviors by a single network state. J Neurosci 33:3786-98
Bai, Lu; Livnat, Itamar; Romanova, Elena V et al. (2013) Characterization of GdFFD, a D-amino acid-containing neuropeptide that functions as an extrinsic modulator of the Aplysia feeding circuit. J Biol Chem 288:32837-51
Sasaki, Kosei; Sasaki, Kosai; Cropper, Elizabeth C et al. (2013) Functional differentiation of a population of electrically coupled heterogeneous elements in a microcircuit. J Neurosci 33:93-105
Dacks, Andrew M; Weiss, Klaudiusz R (2013) Release of a single neurotransmitter from an identified interneuron coherently affects motor output on multiple time scales. J Neurophysiol 109:2327-34
Jing, Jian; Sasaki, Kosei; Perkins, Matthew H et al. (2011) Coordination of distinct motor structures through remote axonal coupling of projection interneurons. J Neurosci 31:15438-49