Faculty Bibliography

OBJECTIVE: Spinal cord injury (SCI) is accompanied by disruption of the blood-spinal cord barrier and subsequent extravasation of fluid and proteins, which results in edema (increased water content) at the site of injury. However, the mechanisms that control edema and the extent to which edema impacts outcome after SCI are not well elucidated. METHODS: Here, we examined the role of aquaporin-4 (AQP4) water channels after experimental contusion injury in mice, a clinically relevant animal model of SCI. RESULTS: Mice lacking AQP4 (AQP4(-/-) mice) exhibited significantly impaired locomotor function and prolonged bladder dysfunction compared with wild-type (WT) littermates after contusion SCI. Consistent with a greater extent of functional deterioration, AQP4(-/-) mice showed greater neuronal loss and demyelination, with prominent cyst formation, which is generally absent in mouse SCI. The extent of spinal cord edema, as expressed by percentage water content, was persistently increased above control levels in AQP4(-/-) mice but not WT mice at 14 and 28 days after injury. Immunohistochemical analysis indicated that blood vessels in the vicinity of the lesion core had incomplete barrier function because of sparse tight junctions. INTERPRETATION: These results suggest that AQP4 plays a protective role after contusion SCI by facilitating the clearance of excess water, and that targeting edema after SCI may be a novel therapeutic strategy

Sensory processing is often regarded as a passive process in which biological receptors like photoreceptors and mechanoreceptors transduce physical energy into a neural code. Recent findings, however, suggest that: first, most sensory processing is active, and largely determined by motor/attentional sampling routines; second, owing to rhythmicity in the motor routine, as well as to its entrainment of ambient rhythms in sensory regions, sensory inflow tends to be rhythmic; third, attentional manipulation of rhythms in sensory pathways is instrumental to perceptual selection. These observations outline the essentials of an Active Sensing paradigm, and argue for increased emphasis on the study of sensory processes as specific to the dynamic motor/attentional context in which inputs are acquired

Epilepsy in women is influenced by endocrine status and antiepileptic drugs (AEDs), but without an animal model, the effects of endocrine variables and AEDs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally-induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague-Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE, and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared to previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE

After it was first identified that seizures increase neurogenesis in the adult brain of laboratory animals, the idea that postnatal neurogenesis may be involved in epilepsy became a topic of widespread interest. Since that time, two perspectives have developed. They primarily address temporal lobe epilepsy (TLE), because the data have either been based on animal models of TLE or patients with intractable TLE. The first perspective is that postnatal neurogenesis contributes to the predisposition for seizures in TLE. This premise is founded in the observations showing that there is a dramatic rise in neurogenesis after many types of insults or injuries which ultimately lead to TLE. As a result of the increase in neurogenesis, several changes in the dentate gyrus occur, and the net effect appears to be an increase in excitability. One of the changes is the formation of a population of granule cells (GCs) that mismigrate, leading to ectopic granule cells in the hilus (hilar EGCs) that exhibit periodic bursts of action potentials, and contribute to recurrent excitatory circuitry. Atypical dendrites also form on a subset of GCs, and project into the hilus (hilar basal dendrites). Hilar basal dendrites appear to preferentially increase the glutamatergic input relative to GABAergic synapses, increasing excitability of the subset of GCs that form hilar basal dendrites. The alternate view is that postnatal neurogenesis is a homeostatic mechanism in epilepsy that maintains normal excitability. This idea is supported by studies showing that some of the new GCs that are born after seizures, and migrate into the correct location, have normal or reduced excitability. Here we suggest that both perspectives may be important when considering a therapeutic strategy. It would seem advantageous to limit the numbers of mismigrating GCs and hilar basal dendrites, but maintain normal neurogenesis because it is potentially homeostatic. Maintaining normal neurogenesis is also important because it has been suggested that a decrease in dentate gyrus neurogenesis contributes to depression. It is challenging to design a strategy that would achieve these goals, and it is also difficult to propose how one could administer such a therapy prophylactically, that is, as an 'antiepileptogenic' approach. Another issue to address is how a therapeutic intervention with these goals could be successful if it were administered after chronic seizures develop, when most patients seek therapy. Although difficult, a number of approaches are possible, and technical advances suggest that there are more on the horizon

We present a simple computational model of the dentate gyrus to evaluate the hypothesis that pattern separation, defined as the ability to transform a set of similar input patterns into a less-similar set of output patterns, is dynamically regulated by hilar neurons. Prior models of the dentate gyrus have generally fallen into two categories: simplified models that have focused on a single granule cell layer and its ability to perform pattern separation, and large-scale and biophysically realistic models of dentate gyrus, which include hilar cells, but which have not specifically addressed pattern separation. The present model begins to bridge this gap. The model includes two of the major subtypes of hilar cells: excitatory hilar mossy cells and inhibitory hilar interneurons that receive input from and project to the perforant path terminal zone (HIPP cells). In the model, mossy cells and HIPP cells provide a mechanism for dynamic regulation of pattern separation, allowing the system to upregulate and downregulate pattern separation in response to environmental and task demands. Specifically, pattern separation in the model can be strongly decreased by decreasing mossy cell function and/or by increasing HIPP cell function; pattern separation can be increased by the opposite manipulations. We propose that hilar cells may similarly mediate dynamic regulation of pattern separation in the dentate gyrus in vivo, not only because of their connectivity within the dentate gyrus, but also because of their modulation by brainstem inputs and by the axons that 'backproject' from area CA3 pyramidal cells. (c) 2008 Wiley-Liss, Inc

Estrogen has diverse and powerful effects in the brain, including actions on neurons, glia, and the vasculature. It is not surprising, therefore, that there are many changes in the female brain as serum estradiol levels rise and fall during the normal ovarian cycle. At times of life when estradiol levels change dramatically, such as puberty, postpartum, or menopause, there also are dramatic changes in the central nervous system. Changes that occur because of fluctuations in serum estrogen levels are potentially relevant to neurological disorders because symptoms often vary with the time of the ovarian cycle. Moreover, neurological disorders (eg, seizures and migraine) often increase in frequency in women when estradiol levels change. In this review, the contribution of 2 growth factors targeted by estrogen, the neurotrophin brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), will be discussed. Estrogen-sensitive response elements are present on the genes for both BDNF and VEGF, and they are potent modulators of neuronal, glial, and vascular function, making them logical candidates to mediate the multitude of effects of estrogen. In addition, BDNF induces neuropeptide Y, which has diverse actions that are relevant to estrogen action and to the same neurological disorders

Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes

Previous studies have shown that VEGF expression in forebrain increases after experimental manipulations that increase neuronal activity. One question is whether this also occurs in motor neurons. If so, it could be potentially advantageous from a therapeutic perspective, because VEGF prevents motor neuron degeneration. Therefore, we asked whether endogenous VEGF expression in motor neurons could be modulated. We also asked how VEGF exposure would influence motor neurons using electrophysiology. Immunocytochemistry showed that motor neuron VEGF expression increased after a stimulus that increases neuronal and motor activity, i.e., convulsive seizures. The increase in VEGF immunoreactivity occurred in all motor neuron populations that were examined 24h later. This effect was unlikely to be due to seizure-induced toxicity, because silver degeneration stain did not show the typical appearance of a dying or dead neuron. To address the effects of VEGF on motor neuron function, VEGF was applied directly to motor neurons while recording intracellularly, using a brainstem slice preparation. Exposure to exogenous VEGF (200 ng/ml) in normal conditions depressed stimulus-evoked depolarization of hypoglossal motor neurons. There was no detectable effect of VEGF on membrane properties or firing behavior. We suggest that VEGF is upregulated in neurons when they are strongly activated, and VEGF depresses neuronal excitation as a compensatory mechanism. Failure of this mechanism may contribute to diseases that involve a dysregulation of VEGF, excessive excitation of motor neurons, and motor neuron loss, such as amyotrophic lateral sclerosis (ALS)