The Journal of Neuroscience, January 1, 2000, 20(1):438–445 Long-Term Depression and Depotentiation in the Sensorimotor Cortex of the Freely Moving Rat David J. Froc, C. Andrew Chapman, Christopher Trepel, and Ronald J. Racine Department of Psychology, McMaster University, Hamilton, Ontario L8S 4K1, Canada Activity-dependent reductions in synaptic efficacy are central duced by ipsilateral stimulation (hours vs days). Although ipsi- components of recent models of cortical learning and memory. lateral LTD was effectively induced by a single session of low- Here, we have examined long-term synaptic depression (LTD) frequency stimulation, multiple sessions of stimulation, either and the reversal of long-term potentiation (depotentiation) of massed or spaced, induced LTD effects that were larger in field potentials evoked in sensorimotor cortex by stimulation of magnitude and longer lasting. Previously, we showed that the the white matter in the adult, freely moving rat. Prolonged, induction of long-term potentiation in the neocortex of chronic low-frequency stimulation (1 Hz for 15 min) was used to induce preparations required multiple, spaced stimulation sessions to either depotentiation or LTD. LTD was expressed as a reduction reach asymptotic levels. Here, we report that LTD also required in the amplitude of both monosynaptic and polysynaptic field multiple stimulation sessions to reach asymptotic levels, but potential components. Both LTD and depotentiation were reli- massed and spaced patterns of low-frequency stimulation were ably induced by stimulation of the ipsilateral white matter. equally effective. Stimulation of the contralateral neocortex induced only a de- Key words: neocortex; long-term potentiation; LTP; LTD; potentiation effect, which decayed more rapidly than that in- plasticity; memory Various neural network models incorporate rules for the bidirec- neocortex, particularly in the awake, freely moving rat (Racine et tional modification of synaptic weights that are based on varia- al., 1995; Beiko and Cain, 1998; Trepel and Racine, 1998). Neo- tions of the “Hebb synapse” (Hebb, 1949). These bidirectional cortical LTP induction in the awake animal requires that the learning rules specify that connection weights will be increased or stimulation be spaced and repeated. Unlike hippocampal LTP, decreased depending on whether the presynaptic and postsynap- which can reach asymptotic levels in one stimulation session, tic activity is correlated or uncorrelated, respectively (Brown et stimulation of the white matter must be distributed over 7–12 d to al., 1990). Such rules prevent the saturation of enhanced connec- maximize LTP in sensorimotor cortex (Trepel and Racine, 1998). tion weights and maintain the capacity of the circuit to store new Using this paradigm, neocortical LTP is as reliable as hippocam- information. pal LTP. The implementation of bidirectional learning rules in real The literature is not entirely consistent, however, regarding the neuronal circuits requires mechanisms that support both in- induction of LTD and depotentiation, at least in the hippocam- creases and reductions in synaptic strength. Experimentally, in- pus. Stimulation protocols that successfully induced LTD and creases in synaptic strength can be induced by brief, high- depotentiation in the dentate gyrus in vitro were ineffective in vivo frequency stimulation of afferent pathways, whereas prolonged (Errington et al., 1995; Abraham et al., 1996). In the freely low-frequency stimulation leads to reductions in synaptic drive. moving rat, prolonged low-frequency stimulation of hippocampal These phenomena are referred to as long-term potentiation and area CA1 has been reported to produce a number of outcomes, long-term depression (LTD). Depression of potentiated re- including reliable LTD (Manahan-Vaughan, 1997), depotentia- sponses is referred to as depotentiation. tion but no LTD (Staubli and Lynch, 1990; Doyle et al., 1997), or Long-term synaptic potentiation (LTP) is currently the most neither depotentiation nor LTD (Errington et al., 1995). Both widely investigated model of the synaptic mechanisms underlying LTD (Thiels et al., 1994; Heynen et al., 1996) and depotentiation memory formation in the mammalian brain (Bliss and Lomo, (Heynen et al., 1996) have been successfully induced in area CA1 1973; Tsumoto, 1992; Bliss and Collingridge, 1993). Although it in the anesthetized in vivo preparation. Staubli and Scafidi (1997), can be reliably induced in the hippocampus in slice, acute, and on the other hand, were unable to induce LTD in this preparation chronic preparations, it has often been difficult to induce in the using similar patterns of stimulation, and Barrionuevo et al. (1980) could only induce depotentiation. Received June 18, 1999; revised Sept. 3, 1999; accepted Sept. 28, 1999. The few demonstrations of LTD or depotentiation in the neo- This research was supported by a grant from the Canadian Natural Sciences and Engineering Research Council. cortex have been conducted in slice (Kirkwood and Bear, 1994b; Correspondence should be addressed to R. J. Racine, Department of Psychology, Castro-Alamancos et al., 1995) or anesthetized (Tsumoto and McMaster University, Hamilton, Ontario L8S 4K1, Canada. E-mail: Suda, 1979; Burette et al., 1997) preparations. In this paper, we [email protected]. Dr. Trepel’s present address: Department of Physiology, University of California, demonstrate reliable long-term depression and depotentiation of Box 0444, 513 Parnassus Avenue, University of California at San Francisco, San field potentials recorded from the sensorimotor cortex of the Francisco, CA 94143-444. chronically prepared rat. The use of this preparation also allowed Dr. Chapman’s present address: Department of Psychology, Concordia Univer- sity, Montreal, Quebec, Canada. us to confirm that the LTD and depotentiation effects were long Copyright © 1999 Society for Neuroscience 0270-6474/99/190438-08$15.00/0 lasting and to examine some of the stimulation parameters that Froc et al. • Neocortical LTD and Depotentiation J. Neurosci., January 1, 2000, 20(1):438–445 439 affect the longevity of these effects. Because LTP induction in this Design preparation requires repeated daily sessions of stimulation There were three experiments. The first dealt with both depotentiation (Racine et al., 1995; Trepel and Racine, 1998), we also tested for and LTD effects produced by stimulation of the contralateral homolo- differences in LTD induced by single or multiple stimulation gous site. The second experiment compared depotentiation effects pro- duced by ipsilateral and contralateral stimulation. The third experiment sessions. dealt with LTD induced by ipsilateral white matter stimulation. Parts of this paper have been presented in abstract form (Froc Depotentiation and LTD of the interhemispheric response. The first and Racine, 1995; Froc et al., 1996). experiment examined whether LTP induced in the right sensorimotor cortex by tetanization of the left motor cortex could be reversed or depotentiated by low-frequency stimulation. In addition, low-frequency MATERIALS AND METHODS stimulation applied to unpotentiated animals provided a test for LTD. Animals and surgery Twenty four hours after the second baseline I–O test, LTP was induced in nine animals by 10 d of high-frequency stimulation. The Fifty-four male Long–Evans rats (300–400 gm) from the McMaster high-frequency stimulation was applied directly to the left sensorimotor University Breeding Colonies were used in these experiments. Rats were cortex. An additional eight animals served as unpotentiated controls. anesthetized with Somnotol (sodium pentobarbital, 65 mg/kg i.p.) and Responses were recorded in the homologous site in the right hemisphere. received atropine (1.2 mg/kg) to prevent respiratory distress. Twisted I–O tests were recorded 1 and7dafter LTP induction to confirm that the wire bipolar electrodes were constructed from Teflon-coated stainless potentiation effects were truly long-lasting. Five of the potentiated ani- m steel wire (120 m diameter), and the exposed tips were separated by 1.0 mals were then tested for depotentiation, whereas four of the animals mm for cortical placements and 0.5 mm for the callosal stimulating remained unstimulated to confirm that the potentiation was maintained electrodes. Electrodes were implanted into either the sensorimotor cor- in the absence of low-frequency stimulation. Similarly, four of the unpo- tex (M1 bordering on S1) or the white matter in the same coronal plane. tentiated control animals received low-frequency stimulation to test for Sensorimotor cortex electrodes were placed 2.0 mm anterior to bregma LTD effects in the contralateral field potential. The remaining four and 3.5 or 4.0 mm lateral to the midline at a depth of 2.0 mm from pia control animals served to ensure that the baseline responses remained (Paxinos and Watson, 1997). White matter electrodes were placed 2.0 stable. I–O tests were recorded immediately and 1, 2, and7dafter mm anterior to bregma, 2.0 mm lateral to the midline, at a depth of 3.0 delivery of low-frequency trains to determine the longevity of the depo- mm from pia. Electrode depths were adjusted during surgery to maxi- tentiation and LTD effects. mize field response amplitudes. The electrodes were connected to gold- Depotentiation of ipsilateral versus contralateral responses. The tran- plated pins and inserted into a connector plug that was anchored to the shemispheric depotentiation effects in the previous experiment