The localization of sites of memory formation within the brain has proven to be a formidable task even for simple forms of learning and memory. In order to localize a particular site of memory formation within the brain, the rabbit eyeblink response was classically conditioned while regions of the cerebellum or red nucleus were temporarily inactivated by microinfusions of the gamma-aminobutyric acid agonist muscimol. Cerebellar inactivation completely blocked learning but had no effect on subsequent learning after inactivation, whereas red nucleus inactivation did not prevent learning but did block the expression of conditioned responses. The site of memory formation for this learned response thus appears to be localized within the cerebellum.

To address several fundamental questions regarding how multiwhisker tactile stimuli are integrated and processed by the trigeminal somatosensory system, a novel behavioral task was developed that required rats to discriminate the width of either a wide or narrow aperture using only their large mystacial vibrissae. Rats quickly acquired this task and could accurately discriminate between apertures of very similar width. Accurate discriminations required a large number of intact facial whiskers. Systematic removal of individual whiskers caused a decrease in performance that was directly proportional to the number of whiskers removed, indicating that tactile information from multiple whiskers is integrated as rats gauge aperture width. In different groups of rats, different sets of whiskers were removed in patterns that preferentially left whisker rows or whisker arcs intact. These different whisker removals caused similar decreases in performance, indicating that individual whiskers within the vibrissal array are functionally equivalent during performance of this task. Lesions of the barrel cortex abolished the ability of rats to discriminate, demonstrating that this region is critically involved in this tactile behavior. Interestingly, sectioning the facial nerve, which abolished whisker movements, did not affect the ability to perform accurate discriminations, indicating that active whisker movements are not necessary for accurate performance of the task. Collectively, these results indicate that the trigeminal somatosensory system forms internal representations of external stimuli (in this case, aperture width) by integrating tactile input from many functionally equivalent facial whiskers and that the vibrissal array can function as a fine-grained distance detector without active whisker movements.

Ensemble neuronal activity was recorded in each layer of the whisker area of the primary somatosensory cortex (SI) while rats performed a whisker-dependent tactile discrimination task. Comparison of this activity with SI activity evoked by similar passive whisker stimulation revealed fundamental differences in tactile signal processing during active and passive stimulation. Moreover, significant layer-specific functional differences in SI activity were observed during active discrimination. These differences could not be explained solely by variations in ascending thalamocortical input to SI. Instead, these results suggest that top-down influences during active discrimination may alter the overall functional nature of SI as well as layer-specific mechanisms of tactile processing.

Perhaps the most fundamental issue in the broad field of neuronal substrates of learning and memory concerns the physical/biological mechanisms underlying long-term memory formation, storage, and retrieval in the mammalian brain. Considerable progress has been made in elucidating memory storage mechanisms in simpler invertebrate systems (

The behavioral phenomenon of blocking indicates that the informational relationship between the conditioned stimulus and the unconditioned stimulus is essential in classical conditioning. The eyeblink conditioning paradigm is used to describe a neural mechanism that mediates blocking. Disrupting inhibition of the inferior olive, a structure that conveys unconditioned stimulus information (airpuff) to the cerebellum prevented blocking in rabbits. Recordings of cerebellar neuronal activity show that the inferior olive input to the cerebellum becomes suppressed as learning occurs. These results suggest that the inferior olive becomes functionally inhibited by the cerebellum during conditioning, and that this negative feedback process might be the neural mechanism mediating blocking.

The isomorphic representation of the contralateral whisker pad in the rodent cerebral cortex has served as a canonical example in primary somatosensory areas that the contralateral body surface is spatially represented as a topographic map. By characterizing responses evoked by multiwhisker stimuli, we provide direct evidence that the whisker region of the rat primary somatosensory cortex (SI) integrates information from both contralateral and ipsilateral whisker pads. The proportions of SI neurons responsive to ipsilateral whisker stimuli, as well as their response probabilities, increased with the number of ipsilateral whiskers stimulated. Under bilateral whisker stimulation, the responses of 95% of neurons recorded were affected by stimulation of ipsilateral whiskers. Contralateral tactile responses of SI neurons were profoundly influenced by preceding ipsilateral stimuli and vice versa. This effect depended on both the spatial location and the relative timing of bilateral whisker stimuli, leading to both spatial and temporal asymmetries of interaction. Bilateral whisker stimulation resulted in only modest changes in evoked response latency. Previous ipsilateral stimulation was also shown to affect tactile responses evoked by later ipsilateral stimuli. Inactivation of the opposite SI abolished ipsilaterally evoked responses as well as their influence on subsequently evoked contralateral responses in the intact SI. Based on these results, we conclude that the rat SI integrates information from both whisker pads and propose that such interactions may underlie the ability of rats to discriminate bilateral tactile stimuli. Key words: barrel cortex; bilateral; ipsilateral; integration; interhemispheric transfer; inactivation; topographyThe role of the somatosensory cortex (SI) in integrating separate sources of tactile input has been investigated primarily by inferring from extracellular recordings the spatiotemporal transformations performed on convergent subcortical inputs. The whisker region of the SI in rodents is an ideal model for investigating the issue of cortical integration because of its modular topography, which purportedly reflects the arrangement of contralateral whiskers at the periphery (Woolsey and Van der Loos, 1970;Killackey, 1973). Recordings from SI neurons in temporal interaction studies have provided a basic description of the temporal and spatial attributes of cortical integration elicited by paired contralateral whisker stimuli (Simons, 1985;Simons and Carvell, 1989;Brumberg et al., 1996;Fanselow and Nicolelis, 1999). Such studies suggest that the SI may integrate information across multiple contralateral whiskers to generate behaviorally relevant information regarding the animal's surrounding environment.If the rat is to use tactile information from both sides of its face, left and right whisker information must also be integrated. Comparisons between these separate sources of tactile input would then allow the animal to successfully detect the width of an aperture, or the orientation of ...

Multiple neuron ensemble recordings were obtained simultaneously from both the primary somatosensory (SI) cortex and the ventroposterior medial thalamus (VPM) before and during the combined administration of reversible inactivation of the SI cortex and a reversible subcutaneous block of peripheral trigeminal nerve fibers. This procedure was performed to quantify the contribution of descending corticofugal projections on (i) the normal organization of thalamic somatosensory receptive fields and (ii) the thalamic somatosensory plastic reorganization that immediately follows a peripheral deafferentation. Reversible inactivation of SI cortex resulted in immediate changes in receptive field properties throughout the VPM. Cortical inactivation also significantly reduced but did not completely eliminate the occurrence of VPM receptive field reorganization resulting from the reversible peripheral deafferentation. This result suggests that the thalamic plasticity that is seen immediately after a peripheral deafferentation is dependent upon both descending corticofugal projections and ascending trigeminothalamic projections.Recent studies demonstrate that the cortical sensory reorganization (1) that immediately follows a peripheral deafferentation (2) is also paralleled by simultaneous plasticity at thalamic and other subcortical levels (3, 4). Further, both the spatial and temporal characteristics of novel cortical and thalamic sensory responses are remarkably similar (4). Based on these results, we proposed that immediate and concurrent cortical and subcortical plasticity results from changes in a dynamic equilibrium between both ascending lemniscal and paralemniscal pathways and descending corticofugal projections that converge at all central processing levels of the somatosensory system (3, 5).Herein, we began to test this hypothesis by investigating how reversible inactivation of corticofugal projections affected the immediate thalamic reorganization observed in the rat trigeminal somatosensory system after a reversible peripheral sensory deafferentation induced by subcutaneous injection of lidocaine. We observed that cortical inactivation during this peripheral sensory deafferentation significantly reduced both the percentage of thalamic ventral posterior medial (VPM) neurons exhibiting new unmasked sensory responses and the size of these unmasked responses but did not abolish the occurrence of thalamic reorganization. As described below, these results support our hypothesis by demonstrating that thalamic plasticity is defined by contributions from both ascending trigeminothalamic pathways and descending corticothalamic projections. MATERIALS AND METHODSThe procedures for surgical electrode implants, single unit discrimination, whisker stimulation, and statistical analyses have been described in detail elsewhere (4, 6, 7). Briefly, microwire electrode arrays were chronically implanted in both the infragranular layer of the barrel region of primary somatosensory (SI) cortex (8 microwires per array) and the VP...

Numerous studies from several laboratories report that temporary inactivation of the cerebellar interpositus nucleus and regions of overlying cortex during eye-blink conditioning completely prevents acquisition of the conditioned eye-blink response (CR) without affecting the ability to learn the CR in subsequent training without inactivation. Recently, these results have been challenged by the suggestion that learning was not completely blocked in these studies. Instead, it has been suggested that low levels of responses on test sessions might represent a retarded form of learning caused by drug effects on cerebellar cortex. The present study was designed to address this issue directly. Very low doses of muscimol were used to selectively inactivate the interpositus nucleus of rabbits during five conditioning sessions. Animals performed no significant levels of CRs during those sessions. Training was continued four more sessions without any inactivations to test whether any learning had occurred during the previous five sessions. Detailed analysis of responses during session six revealed that learning was completely blocked by the low doses of muscimol infused into the interpositus during the first five sessions. Animals subsequently acquired the CR normally. These results confirm and extend the original findings that appropriate lesions (either temporary or permanent) of the interpositus nucleus completely prevent acquisition of the conditioned eye-blink response. Other issues regarding reversible inactivation studies are also discussed.