Bilateral cervical contusion spinal cord injury in rats

There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague–Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. Forelimb motor function was assessed using a grip strength meter (GSM); sensory function was assessed by the von Frey hair test; the integrity of the corticospinal tract (CST) was assessed by biotinylated dextran amine (BDA) tract tracing. Mild contusions caused primarily dorsal column (DC) and gray matter (GM) damage while moderate contusions produced additional damage to lateral and ventral tissue. Forelimb and hindlimb function was severely impaired immediately post-injury, but all rats regained the ability to use their hindlimbs for locomotion. Gripping ability was abolished immediately after injury but recovered partially, depending upon the spinal level and severity of the injury. Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted.     

Peripheral and central changes combine to induce motor behavioral deficits in a moderate repetition task

Repetitive motion disorders, such as carpal tunnel syndrome and focal hand dystonia, can be associated with tasks that require prolonged, repetitive behaviors. Previous studies using animal models of repetitive motion have correlated cortical neuroplastic changes or peripheral tissue inflammation with fine motor performance. However, the possibility that both peripheral and central mechanisms coexist with altered motor performance has not been studied. In this study, we investigated the relationship between motor behavior changes associated with repetitive behaviors and both peripheral tissue inflammation and cortical neuroplasticity. A rat model of reaching and grasping involving moderate repetitive reaching with negligible force (MRNF) was used. Rats performed the MRNF task for 2 h/day, 3 days/week for 8 weeks. Reach performance was monitored by measuring reach rate/success, daily exposure, reach movement reversals/patterns, reach/grasp phase times, grip strength and grooming function. With cumulative task exposure, reach performance, grip strength and agility declined while an inefficient food retrieval pattern increased. In S1 of MRNF rats, a dramatic disorganization of the topographic forepaw representation was observed, including the emergence of large receptive fields located on both the wrist/forearm and forepaw with alterations of neuronal properties. In M1, there was a drastic enlargement of the overall forepaw map area, and of the cortex devoted to digit, arm–digits and elbow–wrist responses. In addition, unusually low current amplitude evoked digit movements. IL-1β and TNF-α increased in forearm flexor muscles and tendons of MRNF animals. The increases in IL-1β and TNF-α negatively correlated with grip strength and amount of current needed to evoke forelimb movements. This study provides strong evidence that both peripheral inflammation and cortical neuroplasticity jointly contribute to the development of chronic repetitive motion disorders.     

Differential tactile and motor recovery and cortical map alteration after C4-C5 spinal hemisection

After incomplete spinal cord injury (SCI), the adult central nervous system is spontaneously capable of substantial reorganizations that can underlie functional recovery. Most studies have focused on intraspinal reorganizations after SCI and not on the correlative cortical remodeling. Yet, differential studies of neural correlates of the recovery of sensory and motor abilities may be conducted by segregating motor and somatosensory representations in distinct and topologically organized primary cortical areas. This study was aimed at evaluating the effects of a cervical (C4-C5) spinal cord hemisection on sensorimotor performances and electrophysiological maps in primary somatosensory (S1) and motor (M1) cortices in adult rats. After SCI, an enduring loss of the affected forepaw tactile sensitivity was paralleled by the abolishment of somatosensory evoked responses in the deprived forepaw area within the S1 cortex. In contrast, severe motor deficits in unilateral forelimb were partially restored over the first postoperative month, despite remnant deficits in distal movement. The overall M1 map size was drastically reduced in SCI rats relative to intact rats. In the remaining M1 map, the shoulder and elbow movements were over-represented, consistent with the behavioral recovery of proximal joint movements in almost all rats. By contrast, residual wrist representations were observed in M1 maps of half of the rats that did not systematically correlate with a behavioral recovery of these joint movements. This study highlights the differential potential of ascending and descending pathways to reorganize after SCI.     

Quantitative assessment of forelimb motor function after cervical spinal cord injury in rats: relationship to the corticospinal tract

Approximately 50% of human spinal cord injuries (SCI) are at the cervical level, resulting in impairments in motor function of the upper extremity. Even modest recovery of upper extremity function could have an enormous impact on quality of life for quadriplegics. Thus, there is a critical need to develop experimental models for cervical SCI and techniques to assess deficits and recovery of forelimb motor function. Here, we analyze forelimb and forepaw motor function in rats after a lateral hemisection at C5 and assessed the relationship between the functional impairments and the extent of damage to one descending motor system, the corticospinal tract (CST). Female Sprague-Dawley rats were trained on various behavioral tasks that require the forelimb, including a task that measures gripping ability by the hand (as measured by a grip strength meter, GSM), a food reaching task, and horizontal rope walking. After 8 weeks of post-injury testing, the distribution of the CST was evaluated by injecting BDA into the sensorimotor cortex either ipsi- or contralateral to the cervical lesion. Complete unilateral hemisection injuries eliminated the ability to grip and caused severe impairments in food retrieval by the forepaw ipsilateral to the lesion. There was no indication of recovery in either task. In cases in which hemisections spared white matter near the midline, there was some recovery of forelimb motor function over time. Assessment of rope climbing ability revealed permanent impairments in forelimb use and deficits in hindlimb use and trunk stability. Sensory testing using a dynamic plantar aesthesiometer revealed that there was no increase in touch sensitivity in the affected forelimb. For the cases in which both histological and behavioral data were available, spared forelimb motor function was greatest in rats in which there was sparing of the dorsal CST.     

Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration

Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3–15 s), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury (p < 0.0005), and, significant learning (p < 0.005) and memory deficits (p < 0.05) in the third post-injury week. Between 6 and 72 h, blood–brain barrier breakdown, extensive traumatic axonal injury in the subcortical white matter and thalamus, and focal areas of neurodegeneration in the cortex and hippocampus were observed in both hemispheres of the injured brain. At 8 to 18 days post-injury, reactive astrocytosis in the cortex, axonal degeneration in the subcortical white matter tracts, and degeneration of neuronal cell bodies and processes in the thalamus of both hemispheres were observed; however, cortical volumes were not different between un-injured and injured rat brains. These data suggest that diffuse TBI in the immature rat can lead to ongoing degeneration of both cell soma and axonal compartments of neurons, which may contribute, in part, to the observed sustained cognitive deficits.     

A bilateral cervical contusion injury model in mice: Assessment of gripping strength as a measure of forelimb motor function

Here, we describe a bilateral cervical contusion model for mice. Adult female mice received graded bilateral contusion injuries at cervical level 5 (C5) using a commercially available impactor (the IH device). Three separate experiments were carried out to define conditions that produce impairments in forelimb function without unacceptable impairment of general health. A grip strength meter (GSM) was used to assess gripping ability as a measure of forelimb motor function; lesion size was assessed histologically by staining cross sections for H&E and GFAP. In Experiment 1, mice received injuries of 30 kilodynes (kdyn); these produced minimal deficits on grip strength. In Experiment 2, mice received injuries of 75 kdyn and 100 kdyn. Injuries of 75 kdyn produced transient deficits in gripping that recovered between 3 and 15 days post-injury (dpi) to about 90% of control; injuries of 100 kdyn produced deficits that recovered to about 50% of control. In Experiment 3, none of the mice that received injuries of 100 kdyn recovered gripping ability. Histological assessment revealed graded injuries that ranged from damage limited primarily to the dorsal column (DC) to damage to the DC, grey matter, ventral column and lateral column. Most lesions filled in with a fibrous tissue matrix, but fluid-filled cystic cavities were found in 13% of the 100 kdyn injury group and a combination of fibrous-filled/fluid-filled cystic cavities were found in 22% and 38% of the 75-kdyn and 100-kdyn injury groups, respectively. There was minimal urine retention following cervical contusion injuries indicating preservation of bladder function. Our results define conditions to produce graded bilateral cervical contusion injuries in mice and demonstrate the usefulness of the GSM for assessing forelimb motor function after cervical contusions.     

Spinal pathways involved in the control of forelimb motor function in rats

There is increasing interest in developing rodent models for cervical spinal cord injury (SCI) and techniques to assess forelimb motor function. Previously, we demonstrated that in rats, complete unilateral hemisection at cervical level five (C5) permanently eliminated the ability to grip and caused severe impairments in food retrieval by the forepaw ipsilateral to the lesion [Anderson, K.D., Gunawan, A., Steward, O., 2005. Quantitative behavioral analysis of forepaw function after cervical spinal cord injury in rats: Relationship to the corticospinal tract. Exp. Neurol. 194, 161-174]. Here, we analyzed the functional consequences of partial lesions that damaged tracts/cells located in the medial vs. lateral portion of the spinal cord. Female Sprague-Dawley rats were trained on the Grip Strength Meter (GSM) and the food pellet reaching task. Rats then received either a "medial lesion" that destroyed an approximately 0.5 mm wide zone from the midline laterally (which included the dorsal column) or "lateral lesion" that destroyed the lateral column at C5 and were tested for 8 weeks. Rats with histologically-verified medial lesions exhibited a complete loss of gripping ability for 7 weeks post-injury; only 1 of 4 animals exhibited any recovery of grip strength, and this occurred at 54 days. In contrast, rats with lateral lesions exhibited deficits, but the majority (7/10) recovered the ability to grip by 43 days post-injury. Interestingly, when tested on the food retrieval task, rats with medial lesions exhibited deficits that recovered; rats with lateral lesions exhibited more permanent deficits. These results suggest that different spinal circuits are involved in recovery of grip strength vs. recovery of skilled reaching.     

Hypoxia–ischemia causes persistent movement deficits in a perinatal rabbit model of cerebral palsy: assessed by a new swim test

The relationship of movement between different muscle groups has not been quantified before in the newborn period. Cerebral palsy (CP), which often occurs as a result of perinatal hypoxia–ischemia (H–I), is categorized depending on clinical presentation, brain region involvement and extent of involvement. In order to test different brain region involvement, this study investigates individual and multi-joint involvement in a rabbit model of CP. Pregnant rabbits at 70% gestation were subjected to 40-min uterine ischemia. Newborn rabbit kits were subjected to a swim test at 5 time points over the first 11 days of life. H–I kits were divided into hypertonic and non-hypertonic groups based on muscle tone at birth. The ranges and velocity of angular movement of the forelimb and hind limb joints (wrist, elbow, shoulder, ankle, knee and hip) during supported swimming were determined. Severely impaired (hypertonic) animals have significantly reduced range and angular velocity of joint motion, which do not improve over time. The non-hypertonic group showed deficits in wrist and hind limb movements that were not evident on prolonged observation. Preventive treatment with an inhibitor of neuronal nitric oxide synthase decreased the incidence of severely impaired kits; the non-hypertonic kits showed a different pattern of swimming. Supported swimming allows quantification of limb and joint motion in the principal plane of movement in the absence of weight bearing and decreases the need for balance control. Identification and quantification of milder deficits allows mechanistic studies in the causation of H–I injury as well as estimation of recovery with therapeutic agents.     

A straight alley version of the BBB locomotor scale

We describe here an alternative procedure for assessing hindlimb locomotor function after spinal cord injury that uses the BBB scale, but tests animals in a reward-baited straight alley rather than an open field. Rats were trained to ambulate in a straight alley and habituated to the open field typically used for BBB open field testing. Three groups of rats were tested. Sprague–Dawley rats received either 200 kD (n = 19) or 300 kD contusions (n = 9) at T9 with the Infinite Horizon device. Fisher rats (n = 8) received moderate contusions (12.5 mm) at T8 with the NYU impactor. BBB scores were assessed at different post-injury intervals in the open field and the straight alley, and scores were compared by correlation analyses. BBB scores in the open field vs. the straight alley were highly correlated (r = 0.90), validating the use of the straight alley for locomotor assessment. Rats exhibited a larger number of bouts of continuous steps in the straight alley vs. the open field (termed passes), providing more opportunities to score hindlimb use and coordination over the 4 min testing interval. Comparisons of scores across days revealed higher day-to-day correlations in the straight alley vs. the open field (r² values of 0.90 and 0.74 for the straight alley and open field respectively), revealing that the straight alley yielded more reliable scores.     

Dietary restriction started after spinal cord injury improves functional recovery

Spinal cord injury typically results in limited functional recovery. Here we investigated whether therapeutic dietary restriction, a multi-faceted, safe, and clinically-feasible treatment, can improve outcome from cervical spinal cord injury. The well-established notion that dietary restriction increases longevity has kindled interest in its potential benefits in injury and disease. When followed for several months prior to insult, prophylactic dietary restriction triggers multiple molecular responses and improves outcome in animal models of stroke and myocardial infarction. However, the efficacy of the clinically-relevant treatment of post-injury dietary restriction is unknown. Here we report that “every-other-day fasting” (EODF), a form of dietary restriction, implemented after rat cervical spinal cord injury was neuroprotective, promoted plasticity, and improved behavioral recovery. Without causing weight loss, EODF improved gait-pattern, forelimb function during ladder-crossing, and vertical exploration. In agreement, EODF preserved neuronal integrity, dramatically reduced lesion volume by > 50%, and increased sprouting of corticospinal axons. As expected, blood β-hydroxybutyrate levels, a ketone known to be neuroprotective, were increased by 2–3 fold on the fasting days. In addition, we found increased ratios of full-length to truncated trkB (receptor for brain-derived neurotrophic factor) in the spinal cord by 2–6 folds at both 5 days (lesion site) and 3 weeks after injury (caudal to lesion site) which may further enhance neuroprotection and plasticity. Because EODF is a safe, non-invasive, and low-cost treatment, it could be readily translated into the clinical setting of spinal cord injury and possibly other insults.     

Effects of infant versus adult pyramidal tract lesions on locomotor behavior in hamsters

The role of the pyramidal tract in locomotion was studied in hamsters by analyzing their locomotor behavior after lesions of the medullary pyramidal tract. Animals with lesions either as adults or as infants were compared to determine whether early pyramidotomy results in greater functional recovery. Normal and pyramidotomized animals were filmed during locomotion on a runway consisting of either smooth or rough terrain to assess whether the uneven surface would accentuate locomotor deficits. Frame-by-frame analysis of the filmed behavior during all phases of the step cycle was carried out to determine positions of the joints of the forelimb and hindlimb during locomotion. Accuracy of limb placement on the rough terrain was determined by observations of consecutive step cycles. The results show that lesions of the pyramidal tract in both infant and adult hamsters affect locomotion first by causing a reduction in the yielding phase of the step cycle and second by producing inaccuracies of forelimb placement. Rough terrain accentuates deficits in forelimb placement during locomotion. Animals with lesions as infants and those with lesions as adults show surprisingly similar deficits in locomotion, with the exception that animals with lesions as infants show some behavioral compensation in hindlimb movement by developing a normal degree of yielding at the knee. In contrast, hamsters with lesions as either adults or infants never recover normal forelimb behavior in either yielding at the elbow or accuracy of forelimb placement. These results emphasize the sensorimotor role of the pyramidal tract, even in a relatively stereotyped behavior such as locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Deficits in contralateral and ipsilateral forepaw motor control following unilateral motor cortical ablations in rats

Two force transducers which were interfaced with a minicomputer were used as operant manipulanda to assess changes in peak force and rate of response produced by unilateral motor cortical lesions in rats. Spatial arrangement of the manipulanda permitted a subject to respond on Transducer I exclusively with his left forepaw and on Transducer II exclusively with his right. Permanent deficits as measured by both force and rate of response were observed for the limb contralateral to the lesion. In the forelimb ipsilateral to the lesion rate of response was severely depressed immediately following the lesion and, although there was marked recovery during the 10–12 days following surgery, post-lesion rates never attained pre-lesion levels.     

Movements of the forelimbs of the cat during stepping on a treadmill.

In normal cats stepping on a treadmill an analysis has been made of movements of the scapula, shoulder, elbow, wrist and digits. The scapula is capable of making large and complicated movements over the rib cage. In locomotion they may be resolved into a cyclical, similunar movement of the glenoid cavity in the parasagittal plane of the cat's body. The movements of the scapula are rather constant over a wide range of velocities. They most resemble those of the hip which also shows a delay in the onset of extension and no yield phase. It is suggested that movements of the scapula have a high priority in the execution of locomotion in the forelimbs. The movements at the shoulder tend to parallel those of the elbow. The terms of palmar flexion and dorsiflexion are retained for the movements at the wrist and digits. The rapid phase of palmar flexion corresponds with the flexion phase at the elbow, and the phase of dorsiflexion with the first extension phase at the elbow. Palmar flexion during the second and third extension phases of the more proximal joints would appear to be initiated by contact of the foot with the ground. The sequences of movement at the wrist and digits allow a comparison of the roles of flexor and extensor muscles of the forearm during locomotion and the flexion reflex, which is compatible with the functional and anatomical organization of cervicothoracic segments. With exception of extension at the scapula the movements of the elbow provide an index of the onsets of flexion and extension at the other joints of the forelimb. Modifications are suggested for the Phillippson step cycle of both forelimbs and hindlimbs to include the delayed onset of extension at the scapula and hip and the particular movements of the wrist, digits and toes.     

Does endogenous progesterone promote recovery of chronic sensorimotor deficits following contusion to the forelimb representation of the sensorimotor cortex?

We studied sensorimotor recovery in male, normal-cycling and pseudopregnant female rats following unilateral FL-SMC contusions. Forelimb use (push off before a rear, support against the walls, and landing after a rear) and the foot fault test (foot misplacements during locomotion on an elevated grid) were analyzed from videotapes taken before surgery, and then again on post-surgical days 2 and 36. High endogenous progesterone levels in females at the time of injury did not affect recovery as there were no differences between males, pseudopregnant females and normal-cycling female rats on these behaviors. None of the brain-injured rats recovered symmetrical forelimb use between 2 and 36 days after injury (P>0.05) and they also showed foot misplacements (P>0.05) in the foot fault test. Male and female rats with contusions had fewer mean foot misplacements on day 36 than 2 days after injury (P<0.001), indicating that there was partial recovery on this task. These results were taken to show that there were no sex differences in motor deficits caused by unilateral FL-SMC injury. In addition, higher endogenous progesterone levels in females did not protect them from the chronic sensorimotor deficits caused by unilateral FL-SMC contusions.     

Graded unilateral cervical spinal cord injury in the rat: evaluation of forelimb recovery and histological effects

The purpose of this study was to develop a model of unilateral cervical (C4-C5) spinal cord contusion injury in the rat and to characterize the functional and histological consequences following three injury levels using a new weight-drop spinal cord injury device. We evaluated forepaw/forelimb and hindlimb functions by: (1) a horizontal ladder beam measuring paw misplacements and slips; and (2) the forelimb preference test which measures the forelimb used for pushing off to rear, for support, and to land on after rearing. Rats with a mild spinal cord injury displayed primarily a forepaw deficit (forepaw misplacements) for 8 weeks after injury. Paw preference also improved after injury, but failed to reach control levels even after 12 weeks. These rats had damage primarily to the rubrospinal, spinocervicothalamic, and the uncrossed lateral corticospinal tracts in the dorsolateral funiculus a well as some loss of the lateral spinothalamic tracts in the lateral funiculus. Rats with a moderate injury had a prominent forepaw deficit still evident at 12 weeks after injury as well as a mild but not significant hindlimb deficit. Paw preference improved slightly 12 weeks. There was a larger lesion in the dorsolateral and lateral funiculi than in mildly injured rats which extended into the ventrolateral funiculi. There was a significant loss of gray matter compared to rats with a mild injury. Rats with a severe injury displayed significant forelimb and hindlimb deficits throughout the 12 week testing period compared to rats with a mild or moderate injury, and also had a more severe paw preference bias (90%). The lesion encompassed the entire dorsolateral, lateral and ventrolateral funiculi with some disruption of the ventral funiculus. There was more significant gray matter necrosis compared to rats with either a mild or moderate injury. Thus, the spinal cord injury device we used may be useful for studying graded cervical spinal cord injury in rats and potential treatments or interventions, because both the behavioral and histological effects are reproducible and consistent.     

Sensitivity of cortical movement representations to motor experience: evidence that skill learning but not strength training induces cortical reorganization

The topography of forelimb movement representations within the rat motor cortex was examined following forelimb strength training. Adult male rats were allocated to either a Power Reaching, Control Reaching or Non-Reaching Condition. Power Reaching rats were trained to grasp and break progressively larger bundles of dried pasta strands with their preferred forelimb. Control Reaching animals were trained to break a single pasta strand and Non-Reaching animals were not trained. Power Reaching animals exhibited a progressive increase in the maximal size of the pasta bundle that could be retrieved during a 30-day training period. Kinematic analyses showed that this improvement was not due to a change in reaching strategy. Intracortical microelectrode stimulation was used to derive maps of forelimb movement representations within the motor cortex of all animals following training. In comparison to Non-Reaching animals, both Power Reaching and Control Reaching animals exhibited a significant increase in the proportion of motor cortex occupied by distal forelimb movement representations (wrist/digit) and a decrease in the proportion of proximal representations (elbow/shoulder). These results demonstrate that the development of skilled forelimb movements, but not increased forelimb strength, was associated with a reorganization of forelimb movement representations within motor cortex.     

NeuroCog FX: Computerized screening of cognitive functions in patients with epilepsy

NeuroCog FX, a computerized neuropsychological screening instrument for serial examinations of patients with epilepsy and other neurological diseases, was developed to fill the gap between unspecific ratings and comprehensive assessments. Eight subtests address attention, working memory, verbal and figural memory, and language. The test duration is less than 30 min. In research contexts, the test can be applied at multiple sites by nonacademic personnel. Normative data were recorded from healthy subjects (N = 244, age range = 16–75 years; retest: N = 44; validation: N = 40) and unselected patients from an epileptology unit (N = 212; retest: N = 94; validation: N = 126). Psychometric analyses confirmed sufficient reliability and concurrent validity, particularly in patients. NeuroCog FX memory and overall performance scores showed “fair” to “good” diagnostic utility with respect to deficits revealed by established tests. NeuroCog FX provides reliable and valid measures of cognitive performance and may be used in clinical and research contexts as a screening instrument.     

The vermicelli handling test: a simple quantitative measure of dexterous forepaw function in rats

Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta [Whishaw IQ, Coles BL. Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 1996;77:135–48]. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment.     

Communicating hydrocephalus in adult rats with kaolin obstruction of the basal cisterns or the cortical subarachnoid space

Communicating hydrocephalus (CH) occurs frequently, but clinically-relevant animal models amenable to diagnostic imaging and cerebrospinal fluid shunting are not available. In order to develop and characterize models of subarachnoid space (SAS) obstruction at the basal cisterns (BC) or cerebral convexities (CX), 25% kaolin was injected in adult female Sprague–Dawley rats following halothane anesthesia; intact- or saline-injected animals served as controls. For BC animals (n = 28 hydrocephalics, n = 20 controls), an anterior approach to the C1-clivus interval was employed and 30 μl of kaolin or saline was injected. For CX injections (n = 13 hydrocephalics, n = 3 controls), 50–60 μl of kaolin was injected bilaterally after separating the partitions in the SAS. In BC-injected rats, kaolin was observed grossly in the basal cisterns but not in the cisterna magna or at the foramina of Luschka, indicating that communicating (or extra-ventricular) – not obstructive – hydrocephalus had been induced. Following ketamine/xylazine anesthesia, magnetic resonance imaging (MRI) of gadolinium injected into the lateral ventricle also demonstrated CSF flow from the foramina of Luschka. MRI also revealed that ventriculomegaly progressed steadily in BC animals and by 2 weeks post-kaolin the mean Evan's ratio (frontal horn) increased significantly (mean 0.45 compared to 0.31 in intact- and 0.34 in saline-injected controls; p < 0.001 for each). CX animals exhibited kaolin deposits covering approximately 80% of the cerebral hemispheres and developed noticeable ventriculomegaly (mean Evan's ratio 0.40), which was significant relative to intact animals (p = 0.011) but not saline-injected controls. Surprisingly, ventriculomegaly following CX injections was less severe and much more protracted, requiring 3–4 months to develop compared to ventriculomegaly produced by BC obstruction. No hydrocephalic animals demonstrated obvious neurological deficits, but BC-injected animals that subsequently developed more severe ventriculomegaly exhibited nasal discharges and “coughing” for several days following kaolin injection. The new BC model is relevant because the clinical presentation of CH in children is often associated with obstruction at this site, while the CX model may be more representative of late adult onset normal pressure hydrocephalus.     

Serotonergic Facilitation of Forelimb Functional Recovery in Rats with Cervical Spinal Cord Injury

Serotonergic agents can improve the recovery of motor ability after a spinal cord injury. Herein, we compare the effects of buspirone, a 5-HT_1A receptor partial agonist, to fluoxetine, a selective serotonin reuptake inhibitor, on forelimb motor function recovery after a C4 bilateral dorsal funiculi crush in adult female rats. After injury, single pellet reaching performance and forelimb muscle activity decreased in all rats. From 1 to 6 weeks after injury, rats were tested on these tasks with and without buspirone (1–2 mg/kg) or fluoxetine (1–5 mg/kg). Reaching and grasping success rates of buspirone-treated rats improved rapidly within 2 weeks after injury and plateaued over the next 4 weeks of testing. Electromyography (EMG) from selected muscles in the dominant forelimb showed that buspirone-treated animals used new reaching strategies to achieve success after the injury. However, forelimb performance dramatically decreased within 2 weeks of buspirone withdrawal. In contrast, fluoxetine treatment resulted in a more progressive rate of improvement in forelimb performance over 8 weeks after injury. Neither buspirone nor fluoxetine significantly improved quadrupedal locomotion on the horizontal ladder test. The improved accuracy of reaching and grasping, patterns of muscle activity, and increased excitability of spinal motor–evoked potentials after buspirone administration reflect extensive reorganization of connectivity within and between supraspinal and spinal sensory-motor netxcopy works. Thus, both serotonergic drugs, buspirone and fluoxetine, neuromodulated these networks to physiological states that enabled markedly improved forelimb function after cervical spinal cord injury.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00974-8.Key Words: Serotonin, Spinal cord injury, Buspirone, Fluoxetine, Forelimb