Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat.

Traumatic brain injury (TBI) survivors experience long-term post-traumatic morbidities. In diffuse brain-injured rats, a chronic sensory sensitivity to whisker stimulation models the agitation of TBI survivors and provides anatomical landmarks across the whisker-barrel circuit to evaluate post-traumatic neuropathology. As a consequence of TBI, acute and chronic microglial activation can contribute to degenerative and reparative events underlying post-traumatic morbidity. Here we hypothesize that a temporal sequence of microglial activation states contributes to the circuit pathology responsible for post-traumatic morbidity, and test the hypothesis by examining microglial morphological activation and neuroinflammatory markers for activation states through gene expression and receptor-binding affinity. Adult male, Sprague-Dawley rats were subjected to a single moderate midline fluid percussion injury (FPI) or sham injury. Microglial activation was determined by immunohistochemistry, quantitative real-time PCR and receptor autoradiography in the primary somatosensory barrel field (S1BF) and ventral posterior medial nucleus (VPM) of the thalamus at 7 and 28 days following FPI. Morphological changes indicative of microglial activation, including swollen cell body with thicker, shrunken processes, were evident in S1BF and VPM at 7 and 28 days post-injury. Principally at 7 days post-injury in VPM, general inflammatory gene expression (major histocompatibility complex I, major histocompatibility complex II, translocator protein 18 kDa [TSPO]) is increased above sham level and TSPO gene expression confirmed by receptor autoradiography. Further, CD45, a marker of classical activation, and TGF-ßI, an acquired deactivation marker, were elevated significantly above sham at 7 days post-injury. Daily administration of the anti-inflammatory ibuprofen (20mg/kg, i.p.) significantly reduced the expression of these genes. Evidence for alternative activation (arginase 1) was not observed. Thus, these data demonstrate concomitant classical activation and acquired deactivation phenotypes of microglia in diffuse TBI in the absence of overt contusion or cavitation. Anti-inflammatory treatment may further alleviate the neuropathological burden of post-traumatic inflammation.

Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation.

Cognitive deficits persist in patients who survive traumatic brain injury (TBI). Lateral fluid percussion brain injury in the mouse, a model of human TBI, results in hippocampal-dependent cognitive impairment, similar to retrograde amnesia often associated with TBI. To identify potential substrates of the cognitive impairment, we evaluated regional neuronal loss, regional hippocampal excitability and inhibitory synaptic transmission. Design-based stereology demonstrated an approximate 40% loss of neurons through all subregions of the hippocampus following injury compared with sham. Input/output curves recorded in slices of injured brain demonstrated increased net synaptic efficacy in the dentate gyrus in concert with decreased net synaptic efficacy and excitatory postsynaptic potential-spike relationship in area CA1 compared with sham slices. Pharmacological agents modulating inhibitory transmission partially restored regional injury-induced alterations in net synaptic efficacy. Both evoked and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in surviving dentate granule neurons were smaller and less frequent in injured brains than in uninjured brains. Conversely, both evoked and spontaneous mIPSCs recorded in surviving area CA1 pyramidal neurons were larger in injured brains than in uninjured brains. Together, these alterations suggest that regional hippocampal function is altered in the injured brain. This study demonstrates for the first time that brain injury selectively disrupts hippocampal function by causing uniform neuronal loss, inhibitory synaptic dysfunction, and regional, but opposing, shifts in circuit excitability. These changes may contribute to the cognitive impairments that result from brain injury.

Spatial tuning curves along the chick basilar papilla in normal and sound-exposed ears.

Intense sound exposure destroys chick short hair cells and damages the tectorial membrane. Within a few days postexposure, signs of repair appear resulting in nearly complete structural recovery of the inner ear. Tectorial membrane repair, however, is incomplete, leaving a permanent defect on the sensory surface. The consequences of this defect on cochlear function, and particularly frequency analysis, are unclear. The present study organizes the sound-induced discharge activity of cochlear nerve units to describe the distribution of neural activity along the tonotopic axis of the basilar papilla. The distribution of this activity is compared in 12-day postexposed and age-matched control groups. Spontaneous activity, tuning curves, and rate-intensity functions were measured in each unit. Discharge activity at 60 frequency and intensity combinations was identified in the tuning curves of hundreds of units. Activity at each of these criterion frequency/intensity combinations was plotted against the unit's characteristic frequency to construct spatial tuning curves (STCs). The STCs depict tone-driven cochlear nerve activity along the length of the papilla. Tuning sharpness, low- and high- frequency slopes, and the maximum response were quantified for each STC. The sharpness of tuning increased with increasing criterion frequency. However, within a frequency, increasing sound intensity yielded more broadly tuned STCs. Also, the high-frequency slope was consistently steeper than the low-frequency slope. The STCs of exposed ears exhibited slightly less frequency selectivity than control ears across all frequencies and larger maximum responses for STCs with criterion frequencies spanning the tectorial membrane defect. When rate-intensity types were segregated, differences were observed in the STCs between saturating and sloping-up units. We propose that STC shape may be determined by global mechanical events, as well as localized tuning and nonlinear processes associated with individual hair cells. The results indicated that 12 days after intense sound exposure, global and local contributions to spatially distributed neural activity are restored.

Mechanisms of mitochondria-neurofilament interactions.

Mitochondria are localized to regions of the cell where ATP consumption is high and are dispersed according to changes in local energy needs. In addition to motion directed by molecular motors, mitochondrial distribution in neuronal cells appears to depend on the docking of mitochondria to microtubules and neurofilaments. We examined interactions between mitochondria and neurofilaments using fluorescence microscopy, dynamic light scattering, atomic force microscopy, and sedimentation assays. Mitochondria-neurofilament interactions depend on mitochondrial membrane potential, as revealed by staining with a membrane potential sensitive dye (JC-1) in the presence of substrates/ADP or uncouplers (valinomycin/carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone) and are affected by the phosphorylation status of neurofilaments and neurofilament sidearms. Antibodies against the neurofilament heavy subunit disrupt binding between mitochondria and neurofilaments, and isolated neurofilament sidearms alone interact with mitochondria, suggesting that they mediate the interactions between the two structures. These data suggest that specific and regulated mitochondrial-neurofilament interactions occur in situ and may contribute to the dynamic distribution of these organelles within the cytoplasm of neurons.

Effects of chronic, post-injury Cyclosporin A administration on motor and sensorimotor function following severe, experimental traumatic brain injury.

PURPOSE: Cyclosporin A (CsA) is widely used in clinical situations to attenuate graft rejection following organ and central nervous system transplantation. Previous studies demonstrated that CsA administration is neuroprotective in models of traumatic brain injury (TBI). However, no studies, to date, have evaluated the influence of post-injury CsA administration on behavioral recovery after TBI. METHODS: Rats (n = 33) were anesthetized and subjected to severe, lateral fluid percussion brain injury. Fifteen minutes thereafter, animals were randomized to receive the first of 28 daily injections of either CsA (10 mg/kg, ip) or saline. Sham-operated animals (n = 14) were anesthetized and surgically prepared without injury and treated daily either with CsA or saline. Motor and sensorimotor functions were assessed at one day before and two days after injury, and weekly thereafter up to 4 wks post-injury. Cognition was assessed at 1 and 4 wks post-injury using a Morris Water Maze test. RESULTS: Injured animals showed significant impairments in motor, sensorimotor and cognitive function over the 4-week post-injury period. Injured animals treated with CsA showed a significant improvement in motor function assessed using a composite neuroscore (at day 28) and in sensorimotor function assessed using a sticky paper test (at days 2, 14, and 28) (p < 0.05, when compared to vehicle treated, injured animals). No beneficial effects on cognitive function were observed following CSA administration. CONCLUSION: These data suggest that daily post-injury treatment with CsA improves certain aspects of motor and sensorimotor function following experimental TBI.

Increased incidence of dyskinesias and other behavioral effects of re-exposure to neuroleptic treatment in social colonies of Cebus apella monkeys.

RATIONALE: Typical neuroleptic medications are still administered to as many as 40% of patients receiving antipsychotic treatment in the US. Intermittent administration or interruption of long-term neuroleptic medication for schizophrenia may increase the incidence of human tardive dyskinesias, and similarly may produce increasingly marked motor side-effects, parkinsonism, and other behavioral pathologies in non-human primates. OBJECTIVES AND METHODS: Given these similarities, we addressed the issue of prolonged and intermittent typical neuroleptic treatment and dopaminergic function during a 5-year, multi-phase study with social colonies of Cebus apella monkeys. In the previously reported phase 1, we examined the effects of 48 weeks of exposure to, followed by withdrawal from, fluphenazine decanoate (FPZ). Phase 3 reported here examined the effects of 18 weeks of re-exposure to FPZ in these same monkeys, 91 weeks after discontinuation of their phase 1 FPZ treatment. RESULTS: Analysis of blood plasma FPZ indicated levels of 0.22+/-0.08 ng/ml for the six injections during the re-exposure period (n=54), comparable to the 0.24+/-0.07 ng/ml levels measured during our original treatment with this dose. Acute dyskinesias and dystonias increased by 300% upon re-exposure to FPZ; 15 of 18 FPZ-treated animals exhibited oral-buccal dyskinesias and all exhibited torticollis or retrocollis. Retreatment with FPZ was also associated with highly significant reductions in Self- and Environment-Directed Behavior and Directed Affiliation, effects similar to those seen during the original phase 1 FPZ treatment. Although FPZ re-treatment was associated with a significant reduction in Directed Aggression (an effect that was more robust than that observed during phase 1), in phase 3, we again observed an increase in Directed Aggression during early drug discontinuation when animals were in a stress-inducing situation. CONCLUSIONS: These results both support our phase 1 conclusion that typical neuroleptic medications may contribute to negative symptoms of schizophrenia and provide additional evidence for the possibility of increased aggression in stressful situations when medication is discontinued. Additionally, the results indicate that intermittent treatment with typical neuroleptics may dramatically increase the incidence of dystonias and dyskinesias.

Distribution of rate-intensity function types in chick cochlear nerve after exposure to intense sound.

Intense sound exposure to the chick ear produces cochlear damage and losses in auditory function. At twelve days post exposure there is considerable structural repair, although a defect on the sensory epithelium remains in the form of an incompletely healed 'patch' lesion. Auditory function significantly recovers 12 days after the exposure, but it, too, is incomplete. In this paper we describe the relationship between stimulus intensity and cochlear nerve discharge rate (the rate-intensity function) in two groups of chicks. One is exposed to damaging sound levels but allowed 12 days to recover, while the other is a group of non-exposed and age-matched control animals. Three different types of rate-intensity functions were identified; saturating, sloping, and straight. The percentage of saturating and sloping functions was compared across all characteristic frequencies in both groups of animals. A significant change was observed in the distribution of these types for recovered units with characteristic frequencies within the region of the patch lesion. In addition, the rate-intensity functions of these units exhibited a steeper slope and a higher maximum response. The distribution of rate-intensity function types and their slope and maximum responses, for units with characteristic frequencies outside of the patch lesion, was similar to those found in control ears. The changes in the cochlear nerve response in exposed chicks may be due to alterations in cochlear mechanics, hair cell or synaptic membrane properties, hair cell innervation, or the loss of a tonic suppression of afferent activity exerted by the damaged short hair cells.

Nutritional management of regurgitation in infants.

Infantile regurgitation is a frequently occurring problem. Throughout the world, anxious parents are imploring physicians to eliminate their infant's regurgitation. General practitioners, pediatricians and pediatric gastroenterologists strive to alleviate infantile regurgitation and its related parental stress. In this paper we define the scope of the problem and analyze the optimal, cost-efficient management approach to simple regurgitation in infants. The intent of this paper is to disseminate this information to practicing physicians and other health care professionals in an attempt to minimize the impact of this annoying problem of infancy and to eliminate confusion and expensive diagnostic tests and use of sub-optimal treatment modalities. Parental reassurance and dietary management by feeding thickened formula are important components in managing regurgitation in infants while maintaining optimal nutritional intake for adequate growth and development.

The pubococcygens and female orgasm: a correlational study with normal subjects.

The relationship of pubococcygeal condition to orgasmic responsiveness in 102 women from a university community was examined in a controlled, prospective investigation. Pubococcygeal strength was measured with a perineometer while responsiveness was assessed by a standardized interview yielding reliable measures of self-reported orgasmic response. Subjects whose responsiveness might have been impaired by such factors as alcohol consumption, inadequate stimulation, and high sexual anxiety were excluded from analyses. Excellent within-session but poor across-session test-retest reliability of the perineometer measures was noted. Initial Strength Contracting proved to be the most reliable measure. Though the majority of the parous women had performed Kegel exercises after delivery, parity was negatively related to pubococcygeal strength on most measures. Contrary to experimental hypotheses, pubococcygeal strength was not found to be positively related to frequency or self-reported intensity of orgasm. Furthermore, women with higher pubococcygeal strength did not report that vaginal stimulation contributed more to attainment of orgasm, nor did they rate vaginal sensations during coitus as more pleasurable. Only in the case of pleasurability of orgasm through clitoral stimulation was a significant, though low, relationship obtained. Possible factors contributing to the discrepancy between these findings and previous uncontrolled investigations are discussed, as are the implications of these findings for the use of Kegel exercises in the treatment of orgasmic dysfunction.

Comparative anatomic study of mandibular growth in rats after bilateral resections of superficial masseter, posterior temporal, and anterior digastric muscles.

Bilateral resections of the superficial masseter, posterior temporal, and anterior digastric muscles of rats were done to determine their effects on mandibular growth. The macroscopic findings support the functional matrix theory of mandibular growth. The analysis of body weight and the statistical two-way analysis of variance done suggest that malnutrition was the main factor that caused the mandibles of rats in the experimental groups of remain undersized.