what really happens in the scn at night

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Journal of Physiology (2001), 532.1 1 What really happens in the SCN at night R. E. J. Dyball and K. Saeb-Parsy Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, UK It is generally believed and clearly stated in most text books of physiology that the cells in the suprachiasmatic nucleus (SCN) of the hypothalamus show a daily variation in their activity and that this is reflected by changes in the spike frequency that can be recorded from the nucleus. Inouye & Kawamura (1979) showed that multiple unit activity recorded from hypothalamic islands increased during the time of day that the animals would have been inactive. A similar rhythm was reported in the activity of cells acutely dissociated from the suprachiasmatic nucleus (Welch et al. 1995) and in intact animals Meier et al. 1998). These studies are, however, incomplete in two respects; first, there is no analysis of the activity either to show that it is rhythmic in the statistically rigorous sense or to define and place confidence limits on the timing of the peaks and troughs of the activity. A new paper by Pennartz and colleagues in this issue of The Journal of Physiology does not address this issue but represents a great leap forward in another direction. They have shown, using rigorous whole-cell recording techniques, that although the number of cells in the SCN which respond to optic nerve stimulation stays constant, there is a difference in the post- stimulus whole-cell membrane current evoked by optic nerve stimulation at different times of day. During the day, the current mediated by the NMDA component of the EPSC in randomly selected cells in the SCN was found less frequently than it was during the night and when it was encountered, its magnitude was significantly smaller in amplitude (see Fig. 1). It is thus likely that despite its relatively low amplitude and slow time course, the NMDA receptor-mediated EPSC might exert a physiological role in modulating the retinal input to the SCN and thus controlling the activity of the cells which represent the circadian oscillator. This finding represents an important addition to our understanding of the daily modulation of the activity of the SCN. A great deal is known of the neurochemical changes which occur in the nucleus at different times of day (see e.g. Inouye & Shibata, 1994). Much recent work on circadian biology in mammals has been directed to determining the interrelation between the mouse equivalents (mPer 1, 2 and 3) of the Drosophila clock gene period (per) and the regulation of their activation by the protein products of another gene, Bmal1, leading to peaks in mPer1 transcription in the day and peaks of Bmal1 transcription at night (see e.g. Dunlap, 1999). Such changes alone do not affect either the activity of the SCN cells or their output. To affect the other regions of the CNS to which SCN cells project, changes in gene transcription must modulate spike intervals. Spike interval coding determines the release of transmitter from axon terminals and this in turn must depend on channel activity and membrane currents. The paper by Pennartz et al. (2001), while it does not establish a direct connection between, for example, the peak in Bmal1 transcription that occurs at night and the expression of the relevant receptor protein, is the first that characterises an important change in the activity of a specific receptor protein. Such changes almost certainly underpin the changes which are known to occur in the activity of the nucleus. It implies that the properties of a given neural pathway in the CNS are not necessarily constant at different times in the light–dark cycle. Thus neural connections are not all hard wired but change quite rapidly with time. Synaptic plasticity (at least in some situations) thus appears to arise from daily alterations in postsynaptic receptor expression. As time goes on we expect to see other reports of associated changes in the activity of different cell surface proteins. DUNLAP, J. C. (1999). Cell 96, 271–290. INOUYE, S. & KAWAMURA, H. (1979). Proceedings of the National Academy of Sciences of the USA 76, 5962–5966. INOUYE, S. & SHIBATA, S. (1994). Neuroscience Research 20, 109–130. MEIER, J. H., WATANABE, K., SCHAAP, J., ALBUS, H. & DETARI, L. (1998). Journal of Neuroscience 8, 9078–9087. PENNARTZ, C. M. A., HAMSTRA, R. & GEURTSEN, A. M. S. (2001). Journal of Physiology 532, 181–194. WELCH, D., LOGOTHETIS, D. E., MEISTER, M. & REPPERT, S. M. (1995) Neuron 14, 697–706. PERSPECTIVES Figure 1 Diagram to illustrate that, during the day, the SCN cells show only a short-duration current in response to optic nerve stimulation (long thin arrow). During the night, however, an additional current blocked by AP5 can also be detected (short broad arrow).

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Journal of Physiology (2001), 532.1 1

What really happens in theSCN at night

R. E. J. Dyball and K. Saeb-Parsy

Department of Anatomy, University ofCambridge, Cambridge CB2 3DY, UK

It is generally believed and clearly stated inmost text books of physiology that the cells inthe suprachiasmatic nucleus (SCN) of thehypothalamus show a daily variation in theiractivity and that this is reflected by changesin the spike frequency that can be recordedfrom the nucleus. Inouye & Kawamura (1979)showed that multiple unit activity recordedfrom hypothalamic islands increased duringthe time of day that the animals would havebeen inactive. A similar rhythm was reportedin the activity of cells acutely dissociatedfrom the suprachiasmatic nucleus (Welch et al.1995) and in intact animals Meier et al. 1998).These studies are, however, incomplete in tworespects; first, there is no analysis of theactivity either to show that it is rhythmic inthe statistically rigorous sense or to define andplace confidence limits on the timing of thepeaks and troughs of the activity. A newpaper by Pennartz and colleagues in this issueof The Journal of Physiology does not addressthis issue but represents a great leap forwardin another direction. They have shown, usingrigorous whole-cell recording techniques, thatalthough the number of cells in the SCN whichrespond to optic nerve stimulation staysconstant, there is a difference in the post-stimulus whole-cell membrane current evokedby optic nerve stimulation at different timesof day. During the day, the current mediated

by the NMDA component of the EPSC inrandomly selected cells in the SCN was foundless frequently than it was during the nightand when it was encountered, its magnitudewas significantly smaller in amplitude (seeFig. 1). It is thus likely that despite itsrelatively low amplitude and slow timecourse, the NMDA receptor-mediated EPSCmight exert a physiological role in modulatingthe retinal input to the SCN and thuscontrolling the activity of the cells whichrepresent the circadian oscillator.

This finding represents an important additionto our understanding of the daily modulationof the activity of the SCN. A great deal isknown of the neurochemical changes whichoccur in the nucleus at different times of day(see e.g. Inouye & Shibata, 1994). Much recentwork on circadian biology in mammals hasbeen directed to determining the interrelationbetween the mouse equivalents (mPer 1, 2 and3) of the Drosophila clock gene period (per)and the regulation of their activation by theprotein products of another gene, Bmal1,leading to peaks in mPer1 transcription in theday and peaks of Bmal1 transcription at night(see e.g. Dunlap, 1999). Such changes alone donot affect either the activity of the SCN cellsor their output. To affect the other regions ofthe CNS to which SCN cells project, changes ingene transcription must modulate spikeintervals. Spike interval coding determinesthe release of transmitter from axon terminalsand this in turn must depend on channelactivity and membrane currents. The paperby Pennartz et al. (2001), while it does notestablish a direct connection between, forexample, the peak in Bmal1 transcription

that occurs at night and the expression of therelevant receptor protein, is the first thatcharacterises an important change in theactivity of a specific receptor protein. Suchchanges almost certainly underpin the changeswhich are known to occur in the activity ofthe nucleus. It implies that the properties of agiven neural pathway in the CNS are notnecessarily constant at different times in thelight–dark cycle. Thus neural connections arenot all hard wired but change quite rapidlywith time. Synaptic plasticity (at least insome situations) thus appears to arise fromdaily alterations in postsynaptic receptorexpression. As time goes on we expect to seeother reports of associated changes in theactivity of different cell surface proteins.

DUNLAP, J. C. (1999). Cell 96, 271–290.

INOUYE, S. & KAWAMURA, H. (1979). Proceedingsof the National Academy of Sciences of the USA76, 5962–5966.

INOUYE, S. & SHIBATA, S. (1994). NeuroscienceResearch 20, 109–130.

MEIER, J. H., WATANABE, K., SCHAAP, J., ALBUS,H. & DETARI, L. (1998). Journal of Neuroscience8, 9078–9087.

PENNARTZ, C. M. A., HAMSTRA, R. & GEURTSEN,A. M. S. (2001). Journal of Physiology 532,181–194.

WELCH, D., LOGOTHETIS, D. E., MEISTER, M. &REPPERT, S. M. (1995) Neuron 14, 697–706.

PERSPECTIVES

Figure 1

Diagram to illustrate that, during the day,the SCN cells show only a short-durationcurrent in response to optic nervestimulation (long thin arrow). During thenight, however, an additional currentblocked by AP5 can also be detected (shortbroad arrow).