Gatsby Computational Neuroscience Unit
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B10 Seminar Room, Alexandra House, 17 Queen Square
London, WC1N 3AR
Supported by The Gatsby Foundation
Cholinergic Regulation of Cortical Function: Physiological and Behavioral Experiments and Computational Modeling
Michael E. Hasselmo
Department of Psychology Center for Memory and Brain, Boston University, USA
Understanding the function of acetylcholine requires interpreting multiple levels of data from physiological, anatomical and behavioral experiments. Computational models provide an essential unifying framework for understanding these data. Data and modeling indicate that acetylcholine regulates the relative influence on cortical circuits of external sensory input versus internal processing, with a particular emphasis on novel stimuli (Hasselmo, 1999). Research in my laboratory and by collaborators has demonstrated modulatory effects of acetylcholine on intrinsic firing properties of cortical neurons (Egorov et al., 2002; Klink and Alonso, 1997), selective modulation of intrinsic but not afferent excitatory synaptic transmission (Hasselmo and Fehlau, 2001; Linster et al., 1999; Hasselmo et al., 1995; Hasselmo and Schnell, 1994), and enhancement of long-term potentiation (Linster et al., 2003; Patil et al., 1998; Hasselmo and Barkai, 1995). These cellular physiological effects can be understood using realistic computational models of cortical function (Linster et al., 2003; Fransen et al., 2002; Hasselmo, 1999; Patil and Hasselmo, 1999; Hasselmo and Wyble, 1997; Hasselmo and Barkai, 1995). The models have been tested with experiments at the behavioral level (McGaughy et al., 2003; Atri et al., 2004; DeRosa et al., 2000; 2001).
Models demonstrate how intrinsic sustained spiking mechanisms in entorhinal cortex (Egorov et al., 2002) could allow active maintenance of novel stimuli (Fransen et al., 2002). This is supported by behavioral data from Jill McGaughy, who showed that cholinergic lesions impair delayed matching of novel but not familiar odors (McGaughy et al., 2003). Models also demonstrate how cholinergic presynaptic inhibition of intrinsic but not afferent transmission enhances the encoding of novel stimuli and reduces interference from previously encoded stimuli (Linster et al., 2003; Hasselmo and Wyble, 1997; Hasselmo and Schnell, 1994). This is supported by behavioral data showing enhancement of proactive interference during cholinergic blockade by scopolamine in both rats (DeRosa and Hasselmo, 2000; DeRosa et al., 2001) and humans (Atri et al., 2004). Modeling also suggested experiments at the physiological level, which demonstrated that cholinergic suppression is stronger for recently potentiated synapses (Linster et al., 2003), consistent with selective cholinergic suppression of "silent" synapses (deSevilla et al., 2003). Norepinephrine also causes a selective presynaptic inhibition of intrinsic synapses which could enhance the relative influence of external input (Hasselmo et al., 1997). The shift in relative influence of external input provides a common circuit level mechanism for the functional role of acetylcholine in both encoding of memory and attention (Hasselmo and McGaughy, 2003).
Acknowledgements: This presentation will include work done with Christiane Linster, Jill McGaughy, Erik Fransen, Angel Alonso and many others.