Biomedical subjects

R F Berman

Publications and source records attributed to R F Berman.

At least 19 recordsLinked to original sources

PubMed2007

Complex, multimodal behavioral profile of the Homer1 knockout mouse.

Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

Analysis of Variance↗

PubMed2005

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Age of Onset↗

PubMed2005

Diffusion-weighted imaging of edema following traumatic brain injury in rats: effects of secondary hypoxia.

Hypoxia and edema are frequent and serious complications of traumatic brain injury (TBI). Therefore, we examined the effects of hypoxia on edema formation after moderate lateral fluid percussion (LFP) injury using NMR diffusion-weighted imaging (DWI). Adult Sprague-Dawley rats were separated into four groups: sham uninjured (S), hypoxia alone (H), trauma alone (T), and trauma and hypoxia (TH). Animals in Groups T and TH received LFP brain injury, with Groups H and TH undergoing 30 min of moderately severe hypoxia (FiO2 = 0.11) immediately after surgery or TBI (respectively). DWIs were obtained at 2, 4, and 24 h and at 1 week post injury, and apparent diffusion coefficient (ADC) maps were constructed. Animals in Groups T and TH showed an early decrease (p < 0.001) in ADC values in the cortex ipsilateral to TBI 4 hr post injury, followed by elevated ADCs 1 week later (p < 0.05). No significant differences in ADC values were seen between T and TH groups in the ipsilateral cortex. In contrast, the ipsilateral hippocampus for Group TH showed only increasing ADC values. This hyperintensity in the ADC map began at 2 h after TBI, was significant by 24 h (p < 0.05), and reached a maximum at 1 week. This hyperintensity was not observed in Group T. Histopathology seen in TBI animals corresponded well with the pathology observed with MRI. Midline shifts reflecting edema were only observed in TBI animals with little difference between normoxic (T) and hypoxic animals (TH). In sum, this study demonstrates that the development and extent of brain edema following TBI can be examined in vivo in rats using DWI technology. TBI resulted in an early decrease in ADC values indicating cytotoxic edema in the cortex that was followed at 1 week by an increase in the ADC that was associated with decreased tissue cellularity. Histopathology corresponded well to the regions of brain injury and edema visualized by T2 and DWI procedures. Overall, the addition of hypoxia to brain injury resulted in a small increase in the magnitude of edema in hippocampus and cortex over that seen with trauma alone.

Animals↗

PubMed2001

Group I metabotropic glutamate antagonist reduces acute neuronal degeneration and behavioral deficits after traumatic brain injury in rats.

Recent studies indicate that acute activation of Group I mGluRs following traumatic brain injury (TBI) contributes to the ensuing pathophysiology. The present study examined the effects of post-TBI administration of the selective mGluR1 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) on acute neuronal degeneration in the hippocampus and long-term sensorimotor and learning/memory outcome. In Experiment 1, 26 rats received 0.4, 2.0, or 10.0 nmol AIDA or artificial CSF vehicle infusion into the hippocampus starting 5 min postinjury. At 24 h after TBI characteristic pyramidal cell degeneration was observed in Fluoro-Jade-stained coronal sections of the CA2/3 sectors of the dorsal hippocampus. The mean (+/-SEM) number of Fluoro-Jade-positive neurons in the 10 nmol AIDA group (184 +/- 32) was significantly less (P < 0.05) than the vehicle group (310 +/- 47). In Experiment 2, 20 rats were trained on sensorimotor and memory tasks prior to parasagittal fluid percussion TBI. Rats were administered 10 nmol AIDA or vehicle as in Experiment 1. Rats were assessed on beam walking and radial arm maze (RAM) performance weekly for 6 weeks after TBI. Acquisition of a Morris water maze (MWM) task was assessed on days 11-15 after TBI. The AIDA-treated group had significantly reduced deficits in beam walk, MWM, and RAM performance compared to the vehicle-treated group. These data indicate that injury-induced acute activation of mGluR1 receptors contributes to both the cellular pathology and the behavioral morbidity associated with TBI.

Animals↗

PubMed2001

The effect of groups II and III metabotropic glutamate receptor activation on neuronal injury in a rodent model of traumatic brain injury.

OBJECTIVE: The role of metabotropic glutamate receptor activation after traumatic brain injury (TBI) is not well understood. In vitro studies suggest that activation of Groups II and III metabotropic glutamate receptors may provide some degree of neuroprotection and may be potential targets for the development of therapeutic strategies. Thus, we examined the effects of Group II and Group III selective agonists on neuronal degeneration after in vivo TBI. METHODS: Fifty male Sprague-Dawley rats were subjected to lateral fluid percussion brain injury immediately followed by an intracranial injection of 2-(2',3')-dicarboxycyclopropylglycine (DCG-IV) (Group II) or (R,S)-4-phosphonophenylglycine (Group III) in the CA2 and CA3 areas of the hippocampus. DCG-IV was injected at doses of 20 fmol, 100 fmol, and 500 fmol, and (R,S)-4-phosphonophenylglycine was injected at 8 nmol, 40 nmol, and 200 nmol. Vehicle injection control groups were used for comparison with each drug group. All animals were killed 24 hours after TBI was induced. Four 50-microm brain sections were obtained from each animal and stained for degenerating neurons with the fluorochrome Fluoro-Jade. Two independent, blinded investigators counted the number of degenerating (Fluoro-Jade-positive) neurons in the CA2 and CA3 areas of the hippocampus of each brain section. RESULTS: Compared with vehicle, the 500-fmol dose of DCG-IV significantly reduced the number of Fluoro-Jade-positive degenerating neurons (P < 0.001). Lower doses of DCG-IV were associated with a decreased but not statistically significant number of Fluoro-Jade-positive neurons. In contrast, (R,S)-4-phosphonophenylglycine had no significant effect on the number of degenerating neurons. CONCLUSION: Administration of selective Group II metabotropic glutamate receptor agonists protects neurons against in vivo TBI. These receptors may thus be a promising target for future neuroprotective drugs.

Animals↗

PubMed2000

Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats.

There is growing pharmacological evidence from several animal models of seizure disorder that adenosine possesses endogenous anticonvulsant activity. In order to further evaluate the role of adenosine in seizure activity, we monitored adenosine and its major biochemical metabolites inosine, xanthine, and hypoxanthine in the dorsal hippocampus by in vivo microdialysis before and during the induction of generalized seizures. Seizures were induced pharmacologically in groups of urethane-anesthetized rats by the administration of bicuculline (0.5 mg/kg, i.v.), kainic acid (12.0 mg/kg, i.v.) or pentylenetetrazol (100-250 mg/kg, i.p). Seizure activity was monitored electrophysiologically from the dorsal hippocampus. Dialysate hippocampal purine levels increased during all three seizure types. The largest increases were for the adenosine metabolites hypoxanthine and inosine, with smaller increases observed for adenosine and xanthine. Intra-hippocampal perfusion with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl-adenine, (EHNA, 300 microM), only slightly increased basal hippocampal adenosine. Guanosine levels in the hippocampus, a purine not directly related to adenosine metabolism, were unaffected by all treatments. These findings demonstrate that an increase in hippocampal adenosine release and metabolism is associated with seizure activity and support the hypothesis that the increased adenosine levels may attenuate hippocampal seizure activity, possibly by terminating ongoing seizures and altering the pattern of subsequent seizures.

Adenine↗

PubMed2000

Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy.

Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by growth retardation, facial dysmorphologies, and a host of neurobehavioral impairments. Neurobehavioral effects in FAS, and in alcohol-related neurodevelopmental disorder, include poor learning and memory, attentional deficits, and motor dysfunction. Many of these behavioral deficits can be modeled in rodents. This paper reviews the literature suggesting that many fetal alcohol effects result, at least in part, from teratogenic effects of alcohol on the hippocampus. Neurobehavioral studies show that animals exposed prenatally to alcohol are impaired in many of the same spatial learning and memory tasks sensitive to hippocampal damage, including T-mazes, the Morris water maze, and the radial arm maze. Direct evidence for hippocampal involvement is provided by neuroanatomical studies of the hippocampus documenting reduced numbers of neurons, lower dendritic spine density on pyramidal neurons, and decreased morphological plasticity after environmental enrichment in rats exposed prenatally to alcohol. Electrophysiological studies also demonstrate changes in synaptic activity in in vitro hippocampal brain slices isolated from prenatal alcohol-exposed animals. Considered together, these observations demonstrate that prenatal exposure to alcohol can result in abnormal hippocampal development and function. Such studies provide a better understanding of neurological deficits associated with FAS in humans, and may also contribute to the development of strategies to ameliorate the effects of prenatal alcohol exposure on behavior.

Animals↗

PubMed2000

Neurobehavioral protection by the neuronal calcium channel blocker ziconotide in a model of traumatic diffuse brain injury in rats.

OBJECT: Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects. METHODS: The authors report that the acceleration-deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7,14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze. CONCLUSIONS: These results demonstrated that the acceleration-deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.

Animals↗

PubMed1999

Electrophysiology of hippocampal CA1 neurons after prenatal ethanol exposure.

In the present study, we examined the longitudinal effects of prenatal ethanol exposure on the electrophysiological characteristics of CA1 neurons in hippocampal slices. Hippocampal slices were obtained from young (25-32-day old) and adult (63-77-day old) male offspring of rats given one of four treatments during gestation. Three groups of pregnant rats were orally intubated with 0, 4, or 6 g/kg ethanol on gestational days 8-20. Caloric intake for the 0- (nutritional control) and 4-g/kg groups was yoked to that of the 6 g/kg group. A fourth group (untreated control) was not intubated, and was given ad lib access to food. Long-term potentiation and paired-pulse inhibition were unaffected by prenatal ethanol exposure in young and adult rats; however, slices taken from the young 6 g/kg ethanol group displayed a significantly lower maximal CA1 population spike amplitude evoked by Schaffer collateral stimulation as compared to young controls. This difference was not observed in adult animals. These data suggest that some aspects of hippocampal physiology are negatively affected in young rats as a result of prenatal ethanol exposure, but this effect reverses as the animal matures.

Aging↗

PubMed1999

ICP monitoring in the rat: comparison of monitoring in the ventricle, brain parenchyma, and cisterna magna.

Various methods of continuous intracranial pressure (ICP) monitoring during experimental procedures in the rat have been described. However, no systematic comparison of ICP monitoring in the ventricle, brain parenchyma, and cisterna magna has been reported. Since accurate and reliable ICP measurements are important in experimental models of traumatic brain injury, the present study was conducted to compare simultaneous ICP measurements from ventricular, cisterna magna, and intraparenchymal monitors during ICP changes. Subdural hematoma was produced by infusion of 0.3 ml of autologous blood into the subdural space over 6 min. The ventricular and the intraparenchymal fiberoptic catheter produced reliable and comparable pressure recordings, that did not statistically differ (p = 0.4), throughout the one hour monitoring time. In contrast, the cisterna magna catheter was less reliable and produced significantly lower readings throughout the monitoring time (p<0.001). The intraparenchymal device produced greater cortical damage than the ventricular catheter. In conclusion, ventricular ICP monitoring is the preferred method under these circumstances, since it is accurate and induces least brain damage.

Animals↗

PubMed1998

Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury.

The effects of diffuse brain injury on dendritic morphology in rat hippocampus and cortex were examined in this study using the recently described impact acceleration model of traumatic brain injury (Marmarou et al., 1994). Dendritic structure was visualized using immunostaining of microtubule associated protein-2 (MAP-2). Brains were studied 24, 48, and 72 h after brain injury. Results from immunohistochemistry and light microscopy indicated a time-dependent disruption of dendritic cytoarchitecture in the CA1 subregion and in the hilus of the hippocampus but not in the dentate gyrus or CA3 subregion. Similar disruption was observed in the cortical mantle overlying the hippocampus. Although disruption of dendritic structure was observed at 24 h, the most severe damage was at 48 h after injury with evidence of at least partial recovery of MAP-2 immunostaining by 72 h. In the most severe damage, dendrites appeared to be fragmented, scattered, and unaligned, consisting of irregularly spaced and darkly stained swollen segments. A mixed pattern of immunostaining was observed in somata of hilar cells, with some appearing normal while others stained only faintly, appearing to have lost their typical polygonal shape. Semiquantitative rankings confirmed these qualitative findings. Immediate post-injury behavioral evaluations of injury severity were compared to the degree of disruption of MAP-2 immunostaining. The results of this study indicate that diffuse brain injury is associated not only with axonal damage but also with injury to dendrites.

Animals↗

PubMed1996

Effects of in vivo perforant path kindling on 0-Mg(2+)-induced CA1 burst activity in rat hippocampal slices.

Previous studies have reported persistent alterations in the electrophysiological characteristics of the CA1 region of the hippocampus after kindling. The present study examined the effects of perforant path kindling on 0-Mg(2+)-induced epileptiform bursting in the CA1 region of hippocampal slices. The duration of evoked bursting was significantly longer in slices taken from kindled animals as compared to those taken from implanted, non-stimulated controls. No significant differences were found in spontaneous burst frequency between slices taken from kindled and control animals. These data suggest that perforant path kindling causes a persistent increase in hyperexcitability in the CA1 region of the hippocampus leading to a facilitation of evoked burst activity perhaps through an enhancement in NMDA-related excitatory neurotransmission.

Animals↗

PubMed1996

Alteration in protein phosphorylation associated with olfactory bulb kindling.

Kindling is a model of neuronal plasticity underlying both epilepsy and memory. One of the cellular mechanisms associated with the increased synaptic efficacy is the modification of the structural configuration of synaptic membrane proteins. The present study examined changes in protein phosphorylation associated with olfactory bulb kindling. The differences in the degree of protein phosphorylation in four brain regions, i.e., olfactory bulb, pyriform cortex, hippocampus and frontal cortex, were examined in kindled, non-kindled and implanted control rats. Two phosphoproteins (45k and 48k, named according to their mol. wt.) in frontal cortex were altered after kindling. There was a two-fold increase in phosphorylation of a 48k phosphoprotein in the frontal cortex of kindled rats compared to controls. This phosphorylation was stimulated by Ca2+/calmodulin, and depressed by ACTH1-24. The 45k phosphoprotein in frontal cortex of kindled rats was decreased to 52% of the controls. The changes in protein phosphorylation found in frontal cortex are consistent with the hypothesis that permanent information storage may reside in cortical areas, while hippocampus and pyriform cortex may be the major relaying centers. This phenomenon could theoretically model an information storage process occurring in the cortex following relay of experiential input from subcortical areas.

Animals↗

PubMed1993

The adenosine binding enhancer, PD 81,723, inhibits epileptiform bursting in the hippocampal brain slice.

The effects of adenosine and the adenosine binding enhancer, PD 81,723, on low magnesium-induced bursting in the in vitro hippocampal slice were examined. Extracellular recordings were obtained from the CA3 pyramidal cell layer while electrically stimulating in the stratum radiatum under low magnesium perfusion. Adenosine (6-100 microM) reduced the duration of epileptiform bursting in a dose-related manner, which was reversible upon washout of adenosine. Application of PD 81,723 (50-100 microM) also resulted in a dose-dependent reduction in the duration of the triggered burst, which was irreversible. These results demonstrate anticonvulsant activity of adenosine and the adenosine binding enhancer, PD 81,723, in the low magnesium model of epilepsy.

Adenosine↗

PubMed1993

Effects of water immersion stress on convulsions induced by pentylenetetrazol.

Increasing durations of water immersion stress were associated with increased serum corticosterone levels, decreased severity of pentylenetetrazol-induced convulsions, and increased latencies to convulse in rats. The results were interpreted in terms of the effects of stress and pentylenetetrazol's actions on GABAergic mechanisms.

Animals↗

PubMed1993

Adenosinergic modulation of the EEG and locomotor effects of the A2 agonist, CGS 21680.

The present study in rats was designed to identify the respective roles of A1 and A2 adenosine receptor activation in the anticonvulsant and behavioral actions of adenosine. Intracaudate injections of the highly selective A2 agonist, CGS 21680, did not affect caudate seizures. However, seizure threshold was increased in the presence of CGS 21680 after blockade of the A1 receptor with CPX, or following activation of the A1 receptor with R-PIA or NECA. Additionally, CGS 21680 led to a dose-related inhibition of locomotor activity when injected into the caudate. These results implicate the involvement of the A2 adenosine receptor in the locomotor depressant actions of adenosine and also suggest possible A2 anticonvulsant effects may depend upon the activation of the A1 receptor.

Adenosine↗

PubMed1993

Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced seizures.

OBJECTIVE: The objective of this study was to determine if magnesium sulfate's central anticonvulsant activity is effective against N-methyl-D-aspartate-induced seizures. STUDY DESIGN: In two separate experiments we investigated magnesium sulfate's ability to inhibit N-methyl-D-aspartate-induced hippocampal seizures in rats. In the first experiment magnesium sulfate was administered peripherally before an intracranial injection of 20 micrograms of N-methyl-D-aspartate. In the second experiment magnesium sulfate was injected intracranially concurrently with N-methyl-D-aspartate. The ability of magnesium sulfate to suppress N-methyl-D-aspartate-induced seizure activity under both conditions was assessed. RESULTS: Peripherally administered magnesium sulfate significantly increased the latency from the time of an N-methyl-D-aspartate injection to the first seizure both by acute injection and after 2 hours of sustained elevation of serum magnesium levels when compared with saline solution-injected controls (p < 0.01). The duration of the first seizure was also significantly reduced. Intracranially administered magnesium sulfate significantly (p < 0.01) increased the seizure latency period by 120%. Overall, central magnesium sulfate prevented seizure activity in 40% of the animals (p < 0.01). CONCLUSION: Magnesium sulfate has a central anticonvulsant action on N-methyl-D-aspartate-induced seizures in this rat model of hippocampal seizures.

Animals↗

PubMed1993

Cerebrovascular responses to soman: time and dose dependent effects.

The effects of convulsant and subconvulsant doses of soman on cerebral blood flow (rCBF) and permeability-capillary surface area products (rPS) were examined in 15 brain regions at 1 hr, 24 hr and 1 week after injection in male, Sprague-Dawley rats. Brain histology was examined 3 days after injection. A convulsant dose of soman (70 micrograms/kg, sc) produced large increases in blood flow in all brain regions 1 hr after injection. Such elevations were still observed in 7/15 brain regions 1 day later and in 2/15 regions (septal area and basal ganglia) 1 week later. Similarly, rPS was significantly elevated in every brain region at 1 hr after injection, in 11/15 brain regions at 24 hr, and 4/15 regions 1 week later. Blood pressure peaked at 1 hr and remained well above control levels (115 mm Hg) for 5 hr after drug administration. A subconvulsant dose of soman (33 micrograms/kg) led to a significant, though less dramatic increase in blood flow in all brain regions within 1 hr but not at 1 day or 1 week after injection. In contrast, rPS increases were generally small except in hind-brain structures at 1 hr and 1 day after agent injection. By 1 week however, rPS values appeared to be rising generally and were significantly elevated in the olfactory bulbs and tubercle, as well as hindbrain regions. At this dose, blood pressures were unchanged from control levels (110-120 mm Hg) at all time periods. At 72 hr following injection of a convulsant dose of soman, severe and extensive cellular changes were found in 11/17 regions. After a subconvulsant dose, such abnormalities were still observed in 6/17 brain regions. The data strongly indicate that soman exposure can produce prolonged regional effects on cerebrovascular functions and neuronal integrity even in the absence of physiologic or behavioral evidence of seizure activity or sustained elevations of blood pressure.

Animals↗