Unilateral brain injury to pregnant rats induces asymmetric neurological deficits in the offspring.

Effects of environmental factors may be transmitted to the following generation, and cause neuropsychiatric disorders including depression, anxiety, and posttraumatic stress disorder in the offspring. Enhanced synaptic plasticity induced by environmental enrichment may be also transmitted. We here test the hypothesis that the effects of brain injury in pregnant animals may produce neurological deficits in the offspring. Unilateral brain injury (UBI) by ablation of the hindlimb sensorimotor cortex in pregnant rats resulted in the development of hindlimb postural asymmetry (HL-PA), and impairment of balance and coordination in beam walking test in the offspring. The offspring of rats with the left UBI exhibited HL-PA before and after spinal cord transection with the contralesional (i.e., right) hindlimb flexion. The right UBI caused the offspring to develop HL-PA that however was cryptic and not-lateralized; it was evident only after spinalization, and was characterized by similar occurrence of the ipsi- and contralesional hindlimb flexion. The HL-PA persisted after spinalization suggesting that the asymmetry was encoded in lumbar spinal neurocircuits that control hindlimb muscles. Balance and coordination were affected by the right UBI but not the left UBI. Thus, the effects of a unilateral brain lesion in pregnant animals may be intergenerationally transmitted, and this process may depend on the side of brain injury. The results suggest the existence of left-right side-specific mechanisms that mediate transmission of the lateralized effects of brain trauma from mother to fetus.

Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury.

Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones ß-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.

Brain trauma or a stroke often lead to severe problems in posture and movement. These injuries frequently occur only on one side, causing asymmetrical motor changes: damage to the left brain hemisphere triggers abnormal contractions of the right limbs, and vice-versa. The injuries can disrupt neural tracts between the brain and the spinal cord, the structure that conveys electric messages to muscles. However, research has also shed light on new actors: the hormones released into the bloodstream by the pituitary gland. Similar to the effects of brain lesions, several of these molecules cause asymmetric posture in healthy rats. In fact, a group of hormones can trigger muscle contraction of the left back leg, and another of the right one. Could pituitary hormones mediate the asymmetric effects of brain injuries? To investigate this question, Lukoyanov, Watanabe, Carvalho, Kononenko, Sarkisyan et al. focused on rats in which the connection between the brain and the spinal cord segments that control the hindlimbs had been surgically removed. This stopped transmission of electric messages from the brain to muscles in the back legs. Strikingly, lesions on one side of the brain in these animals still led to asymmetric posture, with contraction of the leg on the opposite side of the body. These effects were abolished when the pituitary gland was excised. Postural asymmetry also emerged when blood serum from injured rats was injected into healthy animals. The findings suggest that hormones play an essential role in signalling from the brain to the spinal cord. Further experiments identified that two pituitary hormones, ß-endorphin and Arg-vasopressin, induced contraction of the right but not the left hindlimb of healthy animals. In addition, small molecules that inhibit these hormones could block the deficits seen on the right side after an injury on the left hemisphere of the brain. Taken together, these results show that neurons in the spinal cord are not just controlled by the neural tracts that descend from the brain, but also by hormones which have left-right side-specific actions. This unique signalling could be a part of a previously unknown hormonal mechanism that selectively targets either the left or the right side of the body. This knowledge could help to design side-specific treatments for stroke and brain trauma.

Effects of repeated electroconvulsive shock seizures and pilocarpine-induced status epilepticus on emotional behavior in the rat.

Affective symptoms are frequently observed in patients with epilepsy. Although the etiology of these behavioral complications remains unknown, it is possible that brain damage associated with frequent or prolonged seizures may contribute to their development. To address this issue, we examined the behavioral sequelae of repeated brief seizures evoked by electroconvulsive shock (ECS) and compared them with those resulting from prolonged status epilepticus (SE) induced with pilocarpine. Using the open-field and elevated plus-maze tests, we detected the presence of behavioral alterations indicative of elevated levels of anxiety in rats that were administered a course of ECS seizures. Fear conditioning was also enhanced in these animals. However, the rats that had experienced SE exhibited less anxiety-like behavior than controls and were severely impaired in fear conditioning. These results support the notion that brain lesions caused by either brief repeated seizures or SE is sufficient to induce some affective disturbances.

Retrosplenial cortex lesions impair acquisition of active avoidance while sparing fear-based emotional memory.

There is strong evidence that the rat retrosplenial cortex (RC) is implicated in spatial navigation and in learning of both aversive and reward-based discrimination tasks. However, its involvement in other functions subserved by the limbic system to which it belongs has not yet been documented. We compared the performance of rats with bilateral excitotoxic damage to RC with that of control rats in a battery of conventional tests, including an open field, plus maze, fear conditioning, step-through passive avoidance, and two-way active avoidance techniques. In the open field, RC-lesioned rats showed somewhat decreased locomotion in the inner zone and increased defecation, which is suggestive of an anxiogenic effect. However, no differences between groups were detected in the plus-maze and inhibitory avoidance tests. Freezing scores recorded during fear conditioning, as well as during the context and tone tests, which were performed, respectively, 24 and 48 h after conditioning, did not differ between the groups. In contrast, acquisition of the active avoidance response was significantly impaired in rats with damaged RC, regarding both response latency and correctness. These data suggest that although the rat RC may play a role in the regulation of emotional responsiveness to new situations, it does not appear to contribute to emotional memory. They are also consistent with the idea that RC is a part of the limbic system that is involved in the compilation of motor programs for complex stereotyped movements such as approach and avoidance.

Impaired water maze navigation of Wistar rats with retrosplenial cortex lesions: effect of nonspatial pretraining.

Damage to the retrosplenial cortex (RC) impairs the performance of rodents on spatial learning and memory tasks, but the extent of these deficits was previously reported to be influenced by the lesion type, rat strain, and behavioral task used. The present study addressed the issue of whether or not cytotoxic damage to RC impairs place navigation of Wistar rats in the Morris water maze and, if so, whether this is merely attributable to spatial learning deficits or to impaired learning of general (nonspatial) behavioral strategies required to correctly perform this task or both. Behaviorally naive rats with bilateral lesions to RC were significantly impaired relative to sham-lesioned rats both during the period of initial learning of the task and during the later phases of training. In addition, these animals showed enhanced thigmotaxis, indicating that the lesion was associated with considerable abnormalities in nonspatial learning. In contrast, RC-lesioned animals that have been previously familiarized with general task rules in a series of shaping trials did not show more thigmotaxis than did their respective controls. Furthermore, although these rats were still impaired in the middle of the training process, their performance during the period of initial learning as well as by the end of training was found to now be normal. Our results confirm those of earlier studies indicating that RC is important for spatial navigation. The findings herein reported are also consistent with the notion that, in addition to spatial information processing, RC is involved in cognitive processes underlying the ability of subjects to properly respond to general task demands.

Seizure-induced structural and functional changes in the rat hippocampal formation: comparison between brief seizures and status epilepticus.

Prolonged seizures produce death of hippocampal neurons, which is thought to initiate epileptogenesis and cause a disruption of hippocampally mediated behaviors. This study aimed to evaluate behavioral and neuroanatomical changes induced by brief seizures and to compare them with changes induced by prolonged seizures. Adult rats were administered 6 brief seizures, elicited by electroshock (ECS). Prolonged seizures (status epilepticus, SE) were induced by pilocarpine. Two months later, the rats' behavior was tested using the Morris water maze, passive avoidance and active avoidance tests. The number of neurons in the hippocampal formation was estimated using stereological methods. ECS seizures produced loss of neurons, ranging between 14% and 26%, in the dentate hilus, subiculum, presubiculum, parasubiculum, and entorhinal layers III and V/VI. However, the neuron loss caused by SE in the same structures, as well as in the hippocampal CA3 and CA1 fields, ranged between 34% and 50%. SE additionally killed many neurons in the dentate granular layer, postsubiculum and entorhinal layer II. ECS treatment caused mild impairments in spatial learning and passive avoidance, but it was not associated with spontaneous motor seizures. In contrast, SE produced a severe disruption of spatial learning, passive and active avoidance, and led to the development of spontaneous seizures. These data show that both prolonged seizure activity and brief seizures result in structural and functional alterations in the temporal lobe circuits, but those caused by prolonged seizures are considerably more severe. Hippocampal damage elicited by brief seizures does not necessarily lead to spontaneous motor seizures.