Stanley Finger

Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome

Two transgenic strains of mutant mice lacking hypoxanthine-guanidine phosphoribosyltransferase (HPRT) activity were examined behaviorally and neurochemically for phenotypic similarity to the human Lesch-Nyhan syndrome. In this syndrome, male children markedly deficient in the enzyme HPRT develop self-mutilation and severe motoric difficulties, and exhibit a pronounced deficiency of dopamine in the basal ganglia. The HPRT-deficient mice showed no evidence of self-mutilation, no detectable motor impairments on tests selected for sensitivity to basal ganglia dysfunction, and no differences in response to apomorphine. Biochemical analyses revealed significantly lower levels of striatal dopamine in the HPRT-deficient mice than in HPRT normal littermates, but the depletion was only of the order of 19%. The results suggest that mice lacking HPRT activity do not phenotypically resemble children born with the same enzymatic deficiency in part because mutant mouse striatal dopamine levels are not as low as those seen in clinical cases with Lesch-Nyhan disease. In contrast to Lesch-Nyhan children, mice may be able to utilize alternative pathways more effectively to maintain purine and neurotransmitter levels within the ranges required for normal brain development and function.

Environmental Attenuation of Brain-Lesion Symptoms

The present chapter deals with the possibility that some behavioral manifestations of brain damage can be modified by general environmental conditions. Specifically, it examines the hypothesis that brain-lesion effects might be increased or decreased in severity as a function of the level of environmental stimulation before or after damage, or between successive injuries. It might be expected that marked changes in brain lesion symptomatology would follow severe deprivation or exposure to aberrant or very restrictive stimulus conditions. However, deprivation effects, while interesting in their own right, shed only indirect light on how maximum recovery might be achieved. In contrast, exposure to stimulating environments could reveal more information about the recovery potential of an organism after a specific brain lesion. Hence, the effects of enhanced stimulation will be emphasized in this review.

Lesion Momentum and Behavior

In 1836 Marc Dax wrote a short manuscript in which he specifically associated aphasia with lesions of the left cerebral hemisphere. His paper was intended for presentation at a regional medical congress at Montpellier (Joynt and Benton, 1964). There is no evidence, however, that Dax actually attended the conference (Broca himself made personal inquiries), and it was not until 1865 that the manuscript was published by his son, Gustav Dax, also a physician. By this time Marc Dax had been dead for 28 years and Broca’s key papers (1861, 1863, 1865) already had been published.

An Early Description of ADHD (Inattentive Subtype): Dr Alexander Crichton and ‘Mental Restlessness’ (1798)

Reviews of the literature on attention-deficit/hyperactivity disorder (ADHD) typically begin early in the twentieth century with the descriptions provided by paediatrician George Still. Physician Alexander Crichton, however, described all of the essential features of the Inattentive subtype of ADHD more than a century earlier than Still. This article presents a short biography of Crichton, looks at his 1798 publication describing attentional disorders in otherwise healthy individuals, contrasts his medical writing with the moralism of Still, and shows how his thoughts and observations are very much in accord with DSM-IV criteria for the Inattentive subtype of ADHD.

Brain Injury and Recovery

attitude, 80, 82, 84, 344 Acetylcholine, 100, 219, 220, 222, 223, 227, 228, 229, 230 inhibitory effects of, 227 on neurons in normal somatosensory cortex, 223 Aerobic exercise, 279, 290

Discovering Trepanation: The Contribution of Paul Broca

PAUL BROCA WAS an icon of neuroscience and neurosurgery who also happened to be intrigued by trepanned skulls. His anthropological work established that, thousands of years ago, individuals not only trepanned skulls but also successfully performed these operations on living persons. After first commenting on a pre-Columbian Peruvian skull in 1867 (the first case of trepanning on a living person widely recognized as such), he turned to even older trepanned skulls found on French soil. In the 1870s, he theorized that the procedure originated as a means to treat convulsions in infants. As he saw it, Neolithic man attributed such convulsions to evil spirits, for which trepanation provided a ready means of escape. Because simple infantile convulsions resolve on their own, the practice would have seemed successful, and therefore it would have been propagated and expanded by later generations. Brocas theory skillfully integrated his anthropological and medical knowledge and helped to create the exciting environment in which scientists pondered what Neolithic and primitive people really knew regarding the brain and surgery.

Comparison of behavioral effects of nucleus basalis magnocellularis lesions and somatosensory cortex ablation in the rat

Cholinergic neurons in the nucleus basalis region of the forebrain project to various portions of the cerebral cortex, including somatosensory cortex. Degeneration of these neurons and their cortical projections is a major feature of the neuropathology of Alzheimers disease. Injecting an excitotoxin into the basal forebrain to destroy nucleus basalis neurons provides a potentially useful animal model for studying the role of these neurons in Alzheimers disease. Previously, we demonstrated that rats with nucleus basalis excitotoxin lesions performed poorly on a tactile discrimination task and on a test of working memory. In an effort to clarify further the role of impaired memory versus other types of impairment (e.g. disrupted somatosensory processing due to cholinergic deafferentation of somatosensory cortex), we compared a group of rats with bilateral nucleus basalis excitotoxin lesions and a group with bilateral somatosensory cortical ablations on a variety of behavioral tasks. Rats with nucleus basalis lesions performed as well as controls on a battery of neurological tests but exhibited increased emotionality unlike rats with somatosensory cortical ablations which performed poorly on the battery but were not hyperemotional. The two lesion groups were impaired significantly and to a comparable degree in performing two-choice tactile discriminations in a T-maze. In contrast, only rats with nucleus basalis lesions showed deficits in working memory as tested in an eight-arm radial maze. Both lesion groups performed comparably to sham controls on a test of reference memory involving a black/white discrimination in a T-maze. The findings suggest that rats with nucleus basalis lesions manifest disturbances in several of the same spheres (emotionality, somatosensory information processing, memory) that are disrupted in Alzheimers disease and further confirm the utility of the excitotoxin lesion approach for studying the pathophysiology of Alzheimers disease.

Nimodipine enhances new learning after hippocampal damage

Rats were trained to lever press and then were given either bilateral lesions of the hippocampus or control operations. Half of the rats in each group received oral nimodipine, a calcium entry blocker, while the remaining rats received vehicle, over a 14-day period that began the evening of surgery. The rats were studied on a DRL 20-s schedule of reinforcement (differential reinforcement of low rates of responding) that required them to withhold a response for at least 20 s after their last lever press in order to earn a reward. Rats with lesions that did not receive the drug performed poorly on the DRL 20-s schedule. In contrast, rats sustaining the same hippocampal lesions but given the drug showed scores that were virtually equivalent to those of the sham-operated control animals. Similar trends were observed when the rats were then tested on a DRL 40-s schedule of reinforcement. These findings suggest that nimodipine may attenuate the effects of acute, focal brain lesions on new learning of even difficult behavioral and cognitive tasks.

Recovery of Function

Individuals engaged in the study of recovery from brain damage and those looking at the literature in this area from a distance would agree that at present the subject is controversial. In fact, historically minded individuals would point out that this has always been the case. For example, Flourens (1842) believed that recovery could occur, but when one function returned all functions returned. In Broca’s 1865 paper, he argued that one hemisphere could function for the other under certain pathological conditions, and Munk (1877) generated disagreement when he proposed that neighboring zones may take over for injured cortical areas through a process that might best be described as “reeducation.”

Behavioral correlates of vitamin D deficiency.

Rats deprived of vitamin D at weaning were compared to control rats on open field, stabilimeter, radial arm maze and spatial reversal tasks in order to test the hypothesis that vitamin D deficiency alters behavior and learning. The deficient animals engaged in statistically less open field rearing activity and spent more time each day negotiating the radial maze than did the control rats. These findings are consistent with the known influence of vitamin D on the musculoskeletal system. The deprived rats did not differ from the control animals on the learning measures. This would indicate that vitamin D deficiency may not significantly impair cognitive functions in young adult rats.