Motor learning changes GABAergic terminals on spinal motoneurons in normal rats

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The cortex gradually modifies the spinal cord during development, throughout later life, and in response to trauma or disease. The mechanisms of this essential function are not well understood. In this study, weak electrical stimulation of rat sensorimotor cortex increased the soleus H-reflex, increased the numbers and sizes of GABAergic spinal interneurons and GABAergic terminals on soleus motoneurons, and decreased GABA A and GABA B receptor labeling in these motoneurons. Several months after the stimulation ended the interneuron and terminal increases had disappeared, but the H-reflex increase and the receptor decreases remained. The changes in GABAergic terminals and GABA B receptors accurately predicted the changes in H-reflex size. The results reveal a new long-term dimension to corticalspinal interactions and raise new therapeutic possibilities. brain stimulation; spinal cord plasticity; GABAergic terminal, interneuron, and receptor; learning and memory THE IMMEDIATE EFFECTS of cortical neuronal activity on the spinal cord are widely studied (e.g., Alstermark and Isa 2012), but its long-term effects have received much less attention. Nevertheless, during development and throughout life the cortex gradually changes spinal pathways to support the acquisition and maintenance of skills such as locomotion, and impairments in this regulation contribute to the disabilities produced by strokes, spinal cord injuries, and other disorders (Knikou 2010;Wolpaw 2010). The mechanisms of this long-term regulation are poorly understood. We are using long-term cortical regulation of the H-reflex, the electrical analog of the spinal stretch reflex (SSR), as a model for studying this important cortical function. The H-reflex, the simplest behavior of the vertebrate CNS, is produced by a wholly spinal and largely monosynaptic pathway consisting of the primary afferent neuron, the motoneuron, and the synapse between them.In primates and rodents, an operant conditioning protocol can change sensorimotor cortex (SMC) activity and thereby gradually increase or decrease H-reflex size (Wolpaw 2010; Wolpaw and Chen 2009). These larger or smaller reflexes, which persist after conditioning ends, are simple motor skills (i.e., adaptive behaviors acquired through practice; Compact Oxford English Dictionary 1993). The reflex changes are produced and maintained by a complex hierarchy of plasticity at both spinal and supraspinal sites Wolpaw 2010 for review). While much remains to be learned about this hierarchy and the sites and mechanisms of plasticity, it is clear that SMC activity modifies the H-reflex by producing changes in the motoneuron (e.g., in firing threshold), as well as elsewhere in the spinal cord. Recent studies showing that operantly conditioned H-reflex decreases are accompanied by marked changes in GABAergic interneurons in the ventral horn and in GABAergic terminals on spinal motoneurons suggest that changes in GABAergic function may play a key role in producing the motoneuron plasticity directly underlying H-reflex ...

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Cortical stimulation causes long-term changes in H-reflexes and spinal motoneuron GABA receptors

Wang

Chen

et al. 2012

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“…The enhanced oligosynaptic transmission to motoneurons that probably occurs with up-conditioning does not seem to be matched by a comparable reduction of oligosynaptic transmission after down-conditioning . Down-conditioning induces an increase in the number, size, and glutamic acid decarboxylase immunostaining of GABAergic terminals on motoneurons in down-conditioned rats (Wang et al 2004(Wang et al , 2006. Opposite changes are not seen in upconditioned rats (Wang et al 2004).…”

Section: Different Mechanisms For Up-and Down-conditioningmentioning

confidence: 99%

H-Reflex Operant Conditioning in Mice

Carp¹,

Tennissen²,

Chen³

et al. 2006

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. Rats, monkeys, and humans can alter the size of their spinal stretch reflex and its electrically induced analog, the H-reflex (HR), when exposed to an operant conditioning paradigm. Because this conditioning induces plasticity in the spinal cord, it offers a unique opportunity to identify the neuronal sites and mechanisms that underlie a well-defined change in a simple behavior. To facilitate these studies, we developed an HR operant conditioning protocol in mice, which are better suited to genetic manipulation and electrophysiological spinal cord study in vitro than rats or primates. Eleven mice under deep surgical anesthesia were implanted with tibial nerve stimulating electrodes and soleus and gastrocnemius intramuscular electrodes for recording ongoing and stimulus-evoked EMG activity. During the 24-h/day computer-controlled experiment, mice received a liquid reward for either increasing (up-conditioning) or decreasing (down-conditioning) HR amplitude while maintaining target levels of ongoing EMG and directly evoked EMG (M-responses). After 3-7 wk of conditioning, the HR amplitude was 133 Ϯ 7% (SE) of control for up-conditioning and 71 Ϯ 8% of control for downconditioning. HR conditioning was successful (i.e., Ն20% change in HR amplitude in the appropriate direction) in five of six up-conditioned animals (mean final HR amplitude ϭ 139 Ϯ 5% of control HR for successful mice) and in four of five down-conditioned animals (mean final HR amplitude ϭ 63 Ϯ 8% of control HR for successful mice). These effects were not attributable to differences in the net level of motoneuron pool excitation, stimulation strength, or distribution of HR trials throughout the day. Thus mice exhibit HR operant conditioning comparable with that observed in rats and monkeys.

“…Although some of this plasticity appears responsible for the mode-appropriate H-reflex change (BelhajSaif and Cheney 2000;Carp and Wolpaw 1994;Curt et al 2002;Feng-Chen and Wolpaw 1996;Pillai et al 2004;Raineteau and Schwab 2001;Wang et al 2006;Wolpaw 1987), the rest of it may ensure the preservation of older behaviors or may simply reflect reactive downstream effects caused by changes in activity associated with plasticity elsewhere (Carp and Wolpaw 1995;Chen et al 2005a,b;Wang et al 2004;Wolpaw and Lee 1989). The plasticity responsible for the paradoxical H-reflex increase seen in Fig.…”

Section: Hrdown Conditioning In Csmc Ratsmentioning

confidence: 99%

Sensorimotor Cortex Ablation Prevents H-Reflex Up-Conditioning and Causes a Paradoxical Response to Down-Conditioning in Rats

Chen

Carp²,

Chen³

et al. 2006

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. Operant conditioning of the H-reflex, a simple model for skill acquisition, requires the corticospinal tract (CST) and does not require other major descending pathways. To further explore its mechanisms, we assessed the effects of ablating contralateral sensorimotor cortex (cSMC). In 22 Sprague-Dawley rats, the hindlimb area of left cSMC was ablated. EMG electrodes were implanted in the right soleus muscle and a stimulating cuff was placed around the right posterior tibial nerve. When EMG remained in a specified range, nerve stimulation just above the M response threshold elicited the H-reflex. In control mode, no reward occurred. In conditioning mode, reward occurred if H-reflex size was above (HRup mode) or below (HRdown mode) a criterion value. After exposure to the control mode for Ն10 days, each rat was exposed for another 50 days to the control mode, the HRup mode, or the HRdown mode. In control and HRup rats, final H-reflex size was not significantly different from initial H-reflex size. In contrast, in HRdown rats, final H-reflex size was significantly increased to an average of 136% of initial size. Thus like recent CST transection, cSMC ablation greatly impaired up-conditioning. However, unlike recent CST transection, cSMC produced a paradoxical response to down-conditioning: the H-reflex actually increased. These results confirm the critical role of cSMC in H-reflex conditioning and suggest that this role extends beyond producing essential CST activity. Its interactions with ipsilateral SMC or other areas contribute to the complex pattern of spinal and supraspinal plasticity that underlies H-reflex conditioning. I N T R O D U C T I O NDuring development and skill acquisition, as well as after spinal cord injury or with other CNS disorders, descending input from the brain combines with peripheral input to change the spinal cord (for reviews see Casabona et al. 1990;Goode and Van Hoven 1982;Koceja et al. 1991;Levinsson et al. 1999;Myklebust et al. 1982Myklebust et al. , 1986Nielsen et al. 1993;O'Sullivan et al. 1991;Straka and Dieringer 1995;Wolpaw and Tennissen 2001). The pathways and processes through which this descending input induces and maintains spinal cord plasticity remain largely unknown. The recently appreciated possibilities for CNS regeneration have raised questions regarding how regenerated neuronal tissue can become useful and how it can be shaped to provide normal, or at least acceptable, function (Wolpaw 2001(Wolpaw , 2002. Thus they have drawn attention to the mechanisms by which the brain gradually shapes spinal cord pathways to function properly during movement (Bregman 1998;Fawcett 1998;Ramer et al. 2000;Tuszynski and Kordower 1999). Understanding these mechanisms could lead to novel methods for inducing, guiding, and assessing recovery after injury.Operant conditioning of the spinal stretch reflex (SSR) or its electrical analog, the H-reflex, is a simple model for studying the brain's induction and maintenance of appropriate spinal cord function (Wolpaw 1997). Because the spinal ...