Rapid functional reorganization of the forelimb cortical representation after thoracic spinal cord injury in adult rats.

Thoracic spinal cord injured rats rely largely on forelimbs to walk, as their hindlimbs are dysfunctional. This increased limb use is accompanied by expansion of the cortical forelimb sensory representation. It is unclear how quickly the representational changes occur and whether they are at all related to the behavioral adaptation. Using blood oxygenation level dependent functional mangetic resonance imaging (BOLD-fMRI) we show that major plastic changes of the somato-sensory map can occur as early as one day after injury. The extent of map increase was variable between animals, and some animals showed a reduction in map size. However, at three or seven days after injury a significant enhancement of the forelimb representation was evident in all the animals. In a behavioral test for precise limb control, crossing of a horizontal ladder, the injured rats relied almost entirely on their forelimbs; they initially made more mistakes than at 7 days post injury. Remarkably, in the individual animals the behavioral performance seen at seven days was proportional to the physiological change present at one day after injury. The rapid increase in cortical representation of the injury-spared body part may provide the additional neural substrate necessary for high level behavioral adaptation.

Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex.

Functional magnetic resonance imaging (fMRI) based on blood oxygen level-dependent (BOLD) contrast is widely used for probing brain activity, but its relationship to underlying neural activity remains elusive. Here, we combined fMRI with fiber-optic recordings of fluorescent calcium indicator signals to investigate this relationship in rat somatosensory cortex. Electrical forepaw stimulation (1-10 Hz) evoked fast calcium signals of neuronal origin that showed frequency-dependent adaptation. Additionally, slower calcium signals occurred in astrocyte networks, as verified by astrocyte-specific staining and two-photon microscopy. Without apparent glia activation, we could predict BOLD responses well from simultaneously recorded fiber-optic signals, assuming an impulse response function and taking into account neuronal adaptation. In cases with glia activation, we uncovered additional prolonged BOLD signal components. Our findings highlight the complexity of fMRI BOLD signals, involving both neuronal and glial activity. Combined fMRI and fiber-optic recordings should help to clarify cellular mechanisms underlying BOLD signals.

Rewiring of hindlimb corticospinal neurons after spinal cord injury.

Little is known about the functional role of axotomized cortical neurons that survive spinal cord injury. Large thoracic spinal cord injuries in adult rats result in impairments of hindlimb function. Using retrograde tracers, we found that axotomized corticospinal axons from the hindlimb sensorimotor cortex sprouted in the cervical spinal cord. Mapping of these neurons revealed the emergence of a new forelimb corticospinal projection from the rostral part of the former hindlimb cortex. Voltage-sensitive dye (VSD) imaging and blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) revealed a stable expansion of the forelimb sensory map, covering in particular the former hindlimb cortex containing the rewired neurons. Therefore, axotomized hindlimb corticospinal neurons can be incorporated into the sensorimotor circuits of the unaffected forelimb.

Functional and anatomical reorganization of the sensory-motor cortex after incomplete spinal cord injury in adult rats.

A lateral hemisection injury of the cervical spinal cord results in Brown-Séquard syndrome in humans and rats. The hands/forelimbs on the injured side are rendered permanently impaired, but the legs/hindlimbs recover locomotor functions. This is accompanied by increased use of the forelimb on the uninjured side. Nothing is known about the cortical circuits that correspond to these behavioral adaptations. In this study, on adult rats with cervical spinal cord lateral hemisection lesions (at segment C3/4), we explored the sensory representation and corticospinal projection of the intact (ipsilesional) cortex. Using blood oxygenation level-dependent functional magnetic resonance imaging and voltage-sensitive dye (VSD) imaging, we found that the cortex develops an enhanced representation of the unimpaired forepaw by 12 weeks after injury. VSD imaging also revealed the cortical spatio-temporal dynamics in response to electrical stimulation of the ipsilateral forepaw or hindpaw. Interestingly, stimulation of the ipsilesional hindpaw at 12 weeks showed a distinct activation of the hindlimb area in the intact, ipsilateral cortex, probably via the injury-spared spinothalamic pathway. Anterograde tracing of corticospinal axons from the intact cortex showed sprouting to recross the midline, innervating the spinal segments below the injury in both cervical and lumbar segments. Retrograde tracing of these midline-crossing axons from the cervical spinal cord (at segment C6/7) revealed the formation of a new ipsilateral forelimb representation in the cortex. Our results demonstrate profound reorganizations of the intact sensory-motor cortex after unilateral spinal cord injury. These changes may contribute to the behavioral adaptations, notably for the recovery of the ipsilesional hindlimb.

Functional reorganization in rat somatosensory cortex assessed by fMRI: elastic image registration based on structural landmarks in fMRI images and application to spinal cord injured rats.

The accuracy at which changes in cortical functional topology can be assessed by functional MRI (fMRI) depends on the quality of the reference coordinate system used for comparison of data sets obtained in different imaging sessions. Current procedures comprise an overlay of activation clusters on registered high-resolution anatomical images. Yet, fMRI images are frequently distorted due to susceptibility artifacts, which are prominent in rodent studies due to the small dimensions involved and high magnetic field strengths used. Therefore, a procedure for co-registration of activation maps has been developed based on anatomical landmarks defined on fMR echo planar images (EPI) themselves. Validation studies in control rats revealed that the centers of activated areas in somatosensory cortex S1, evoked through sensory forepaw stimulation fell within an area of 1 x 1 mm(2) in agreement with known electrophysiological coordinates. The technique was applied to detect changes in activation patterns in rats following smaller unilateral spinal cord injuries (SCI) in their cervical segments (C3/C4) 12 weeks after lesion. Despite of an almost complete behavioral recovery, fMRI responses remained altered in SCI animals with both significantly reduced fMRI signal amplitude and reduced latency to reach the peak response. Moreover, in SCI animals the activated S1 area corresponding to the contralesional forepaw was significantly enlarged and the center-of-mass for the ipsilesional paw was shifted rostrally. The mapping technique described combined with the temporal analysis of the BOLD response enabled a noninvasive quantitative characterization of cortical functional reorganization following SCI in rats.

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact.

RATIONALE: Schizophrenia has been associated with dysregulation of dopamine (DA) transmission and impairment in a number of experimental tasks, including sensorimotor gating assessed using prepulse inhibition (PPI) and selective attention assessed using latent inhibition (LI). We have demonstrated in previous studies that after withdrawal from escalating (ESC) dosages of amphetamine (AMPH), animals exhibited disruption of LI but no alteration of PPI. Moreover, these animals always showed behavioural sensitization to an AMPH challenge. OBJECTIVE: In this study, we were interested in testing whether a different administration schedule would elicit disruption of both LI and PPI. METHODS: Animals were treated with continuous AMPH release (via osmotic mini-pumps at a dosage of 10 mg kg(-1) day(-1) for 7 days) and tested for their performance in L and PPI during withdrawal in a drug free state. Rats received AMPH treatment during the induction phase in their home cages or in the activity chambers. Following withdrawal, the expression of behavioural sensitization to an AMPH challenge was tested in both cases in the activity chambers. RESULTS: Animals pretreated with AMPH from both groups did not exhibit behavioural sensitization. Withdrawal from continuous administration induced LI attenuation with no effect on PPI. CONCLUSIONS: These findings are similar to what was previously found with respect to an ESC AMPH regime. The only difference between the schedules was that the ESC AMPH schedule led to behavioural sensitization whereas the continuous AMPH did not. It is suggested that the expression of sensitization may not be a prerequisite for observed LI disruption.

Differential effects on prepulse inhibition of withdrawal from two different repeated administration schedules of amphetamine.

In this study, rats were tested in behavioural paradigms relevant to schizophrenia during withdrawal from two different administration schedules of amphetamine (Amph). One of the escalating administration schedules, which has been employed in previous studies, consisted of three daily injections for 6 d with increasing dosages from 1 to 5 mg/kg Amph (Esc-5) and was compared to a hitherto never examined escalating administration schedule [three injections per day for 6 d escalating from 1 to 8 mg/kg Amph (Esc-8)]. Control animals received an equivalent volume of saline (Sal) injections according to the same schedule. Whereas rats treated with Esc-5, as reported before, failed to show an effect on prepulse inhibition (PPI), the Esc-8-treated rats exhibited a long-lasting disruption of PPI in a drug-free state on days 6, 13 and 55 of withdrawal. The Amph-pretreated animals demonstrated a similar magnitude of behavioural sensitization following an Amph challenge on withdrawal day 58 irrespective of the administration schedule. To evaluate if the withdrawal from the two Amph schedules led to a change in brain monoamine levels, a subgroup of animals was neurochemically examined in post-mortem for eight parameters in seven brain regions on withdrawal day 55. Withdrawal from the Esc-8 schedule induced reduced dopamine levels in the caudate putamen. Only this neurochemical finding and the PPI attenuation differentiated the Esc-8 animals from the Esc-5 and Sal animals. These data suggest that, based on the endogenous sensitization hypothesis of schizophrenia, the persistent disruption of PPI observed in animals withdrawn from Esc-8 can be used as a valid animal model of specific symptoms of schizophrenic patients.