Organization of Memory Traces in the Mammalian Brain

140

Diverse roles in cellular functions have been ascribed to nitric oxide (NO), and its involvement in induction of long-term depression in cerebellar Purkinje cells has been demonstrated. Manipulations of NO concentration or its synthesis in cerebellar tissues therefore provide a means for investigating roles of NO in cerebellar functions at both cellular and behavioral levels. We tested adaptive control of locomotion to perturbation in cats, and found that this form of motor learning was abolished by application of either an inhibitor of NO synthase or a scavenger of NO to the cerebellar cortical locomotion area. This finding supports the view that NO in the cerebellum plays a key role in motor learning.In the cerebellum, long-term depression (LTD) is persistent reduction of transmission efficacy at synapses from parallel fibers to Purkinje cells, which occurs when the parallel fibers are activated in conjunction with climbing fibers converging onto the same Purkinje cells (1, 2). It has been reported that stimulation of the white matter of the cerebellum enhances nitric oxide (NO) concentration in the molecular layer (3), and that NO activates soluble guanylate cyclase, leading to an increase in the level of cyclic GMP (4, 5). When combined with parallel fiber stimulation, NO donors or cyclic GMP induce LTD-like phenomena in slice preparations (3, 6). LTD and these LTD-like phenomena are abolished by N G -monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, or hemoglobin, a scavenger of NO (3,[7][8][9]. In a recent study, when NO was photolytically released inside Purkinje cells in conjunction with postsynaptic depolarization, LTD was induced as a manner of parallel fiber activation plus depolarization (10). Thus, NO has been proposed to play an important role in signal transduction processes underlying LTD.LTD has been thought to be a cellular basis of motor learning (1). To establish a causal relationship between LTD and actual motor learning, it is prerequisite that a blockade of a biochemical step that is unique to LTD impairs motor learning. As has been reported (11), exposure of one forelimb to a belt velocity higher than that of the other limbs during locomotion of a cat on a treadmill provides an effective means for testing motor learning. Thereby the coordination of limb movements was disturbed, and climbing fiber responses were induced at high probability in Purkinje cells of the cerebellar vermis (12). After a number of steps in the perturbed locomotion, the cats regained interlimb coordination and stability. In view of the findings that the adaptation takes place in decerebrate cats (11), that interlimb coordination is seriously impaired in spinal cats (13,14), and that mechanical lesions or cooling of the cerebellum induces disturbances of locomotion (15-18), the cerebellum is the most likely site responsible for this adaptation. In this study, we investigated the involvement of NO in the adaptation of locomotion by direct localized application of either an inhibitor of NO synthase o...

Section: Neurobiology: Yanagihara and Kondomentioning

confidence: 57%

Nitric oxide plays a key role in adaptive control of locomotion in cat

Yanagihara

Kondo

1996

140

“…1A). On session 7, the first session without infusion, these animals performed the CR at asymptotic levels (1,27,28) using a variety of techniques in different species have consistently reported a similar finding: appropriate lesions of the cerebellum, either temporary or permanent, completely prevent acquisition and expression of the classically conditioned eye-blink response. This effect of cerebellar lesion on the eye-blink CR may be explained in one of two ways: (i) lesions of the cerebellum disrupt an essential memory trace that is localized within the cerebellum or (ii) cerebellar lesions disrupt essential cerebellar output that ultimately projects to the site of memory formation and storage.…”

Section: Resultsmentioning

confidence: 75%

Inactivation of the superior cerebellar peduncle blocks expression but not acquisition of the rabbit's classically conditioned eye-blink response.

Krupa

Thompson

1995

Self Cite

The localization of sites of memory formation within the mammalian brain has proven to be a formidable task even for simple forms of learning and memory.Recent studies have demonstrated that reversibly inactivating a localized region of cerebellum, including the dorsal anterior interpositus nucleus, completely prevents acquisition of the conditioned eye-blink response with no effect upon subsequent learning without inactivation. This result indicates that the memory trace for this type of learning is located either (i) within this inactivated region of cerebellum or (ii) within some structure(s) efferent from the cerebellum to which output from the interpositus nucleus ultimately projects. To distinguish between these possibilities, two groups of rabbits were conditioned (by using two conditioning stimuli) while the output fibers of the interpositus (the superior cerebellar peduncle) were reversibly blocked with microinjections of the sodium channel blocker tetrodotoxin. Rabbits performed no conditioned responses during this inactivation training. However, training after inactivation revealed that the rabbits (trained with either conditioned stimulus) had fully learned the response during the previous inactivation training. Cerebellar output, therefore, does not appear to be essential for acquisition of the learned response. This result, coupled with the fact that inactivation of the appropriate region of cerebellum completely prevents learning, provides compelling evidence supporting the hypothesis that the essential memory trace for the classically conditioned eye-blink response is localized within the cerebellum.Identification of the site or sites of memory formation and storage within the brain for any particular type of memory is an essential prerequisite for elucidating the cellular or subcellular mechanisms as well as the network level properties that mediate the acquisition, retrieval, and expression of that particular memory. Although much progress toward identifying potential sites of memory formation and storage has been achieved, definitive localization of a particular memory locus within the mammalian brain has remained frustratingly elusive. A major obstacle impeding this localization of memory traces is the necessity of first identifying the neural-anatomical circuitry essential for acquisition and expression of a particular learned response. For at least one form of learned behavioraversive, classically conditioned discrete skeletal movements, specifically, the classically conditioned eye-blink responsethe neural circuitry essential for acquisition and expression of the learned response has largely been identified (for review, see ref. 1). In brief, the results of lesion, recording, and stimulation studies indicate that the conditioned stimulus (CS) pathway includes sensory relay nuclei, the pontine nuclei, and mossy fiber projections, via the middle cerebellar peduncle, toThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be he...

“…Thus, we hypothesize that this shift results in a chronic overstimulation of PCs by the parallel fibers, resulting in increased PC firing in vivo. According to the view that an intact LTD at the parallel fiber-PC synapse is required for the optimal efficiency of eyelid conditioning studied as a prototypical reflect of cerebellar learning (15,33), the shift of LTD toward LTP in FAS could also contribute to the deficits in eyelid conditioning and motor learning. Whether the replacement of LTD by LTP in FAS mice constitutes the only cause of LFPO emergence and PCs firing behavior in FAS has not yet been demonstrated, because other mechanisms that involve the PCs and/or other cerebellar neurons could also participate.…”

Section: Discussionmentioning

confidence: 99%

Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

Servais

Hourez²,

Bearzatto³

et al. 2007

In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the ␥-isoform of protein kinase C. Longterm depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of longterm synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder.calcium ͉ cerebellum ͉ protein kinase ͉ long-term depression ͉ motor learning F etal alcohol syndrome (FAS) is the leading cause of intellectual disability in the Western world with a prevalence of 1 to 1.5 cases per 1,000 live births (1) and a lifetime cost of care of approximately $1.4 million per case. This cost is mainly because of ethanol toxicity in the developing central nervous system, causing intellectual disability, deficits in learning, and fine-motor dysfunction (2).The cerebellum is one of the main targets of in utero ethanol toxicity (3). Within the cerebellum, Purkinje cells (PCs) are highly sensitive to ethanol. PCs constitute the sole output of the cerebellar cortex and thus have a central functional role in integration. All animal models of FAS display a reduction in the number of PCs by Ϸ20% (4), and various authors have proposed that neuronal loss is the only cause of cerebellar deficits in FAS. One study conducted on adult anesthetized rats with FAS led to the conclusion that PCs that survive ethanol administration function normally (5). Thomas et al. (6) found a correlation between total PCs number and motor performance. These experimental data led to the assumption that surviving PCs function normally and that motor coordination impairment in FAS results only from a quantitative defect of PCs. This is crucially important from a therapeutic point of view because very few options exist to replace dead neurons. Many studies have therefore focused on different ways to decrease PC loss in FAS (7,8). However, different models of ataxia that result from PC death per se (pcd mice, SV4 mice, T147 transgenic mice) have demonstrated that considerable neuropathology can occur without the manifestation of a neurologic...