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by Kristin Russo & Danielle Owens-Reid It is highly likely that you have friends or express their feelings as easily, or at all, so it's easy to dismiss them after a date #DivorceDrama: 'All my husband knows is to womanise' – Wife tells court. After a half-century practicing law—44 years on the bench, and more than two decades on Michael L. Russo 64C 65L passed away October 5, .. Hubert Franklin "Jim" Owens, age 81 of Canton, GA passed away Sunday October 5, .. With a history dating back to , it is one of the largest law firms in the. This post will explore and offer advice for families who are caring for LGBTQ . to Everyday Life by Danielle Owens-Reid & Kristin Russo– This is a great book to.
Hyperexcitability of cortical and hippocampal structures has recently been identified as one of the mechanisms of cognitive deficits in human aging, Alzheimer's disease AD as well as in animals Models of AD. As underlying cause dysfunction of inhibitory interneurons rather than general neuronal overactivity has been proposed probably associated with mitochondrial dysfunction. In line with these findings, out of several antiepileptics which all reduce neuronal excitability only levetiracetam was able to reduce neuronal hyperexcitability and to improve the associated cognitive defects Methods: Because of its close relationship to the metabolic enhancer piracetam we speculated that levetiracetam similarly improves neuronal function by enhancing mitochondrial function in a cell model of aging, AD, and the interplay of both conditions.
Our findings are fully in line with these assumptions as levetiracetam showed substantial improvement of disturbed mitochondrial paraments as ATP production, mitochondrial dynamics fission and fusion balancemPTP pore opening, as well as impaired neuritogenesis due to mitochondrial defects.
While these data are quite clear, we still were puzzled in respect of a possible mechanism of action of levetiracetam for these effects, as its primary target, the SV2A protein, seems to be closely related to brain synaptic membranes. However, we could clearly identify substantial levels of this protein also at the mitochondrial level. As SV2A works in the brain as a regulator of vesicle fusion we speculated on the basis of our findings that levetiracetam reduces mPTP opening that it might be involved in the complex mechanisms regulating mPTP function which also involve complex fusion mechanisms at the level of the mitochondrial membrane Keywords: Alzheimer's disease AD is the most common form of dementia and is characterized by the progressive decline in cognitive function, with deficits in hippocampal-mediated learning and memory.
These neuropathological changes are associated with striking impairments in synaptic plasticity in the hippocampus, and behavioral assays demonstrate severe impairments in learning and memory in CK-p25 mice. This provides an excellent model for identification of novel approaches that could be used to reverse deficits in synaptic plasticity and cognitive function that occur in neurodegenerative disorders associated with these hallmark neuropathological changes that occur in patients suffering from AD and related disorders.
Glutamate is the primary excitatory neurotransmitter in the CNS and plasticity at glutamatergic synapses is thought to be critical for learning, memory and cognition. Over the past decade, highly selective positive allosteric modulators PAMs of the metabotropic glutamate receptor subtype 5 mGlu5 have emerged as a promising new approach for improving cognitive function in schizophrenia and other non-degenerative CNS disorders.
As opposed to direct activation of mGlu5, PAMs dramatically potentiate the response of the receptor to its endogenous ligand, glutamate, and offer high selectivity while avoiding unwanted side-effects seen with direct activation of the receptor. Interestingly, mGlu5 PAMs enhance specific forms of synaptic plasticity in the hippocampus, as well as hippocampal-dependent forms of learning and memory in wild-type animals that are impaired in CK-p25 mice.
In addition, previous studies suggest that mGlu5 activation can increase synaptogenesis in forebrain regions in which synaptic density is reduced in AD patients and in CK-p25 mice.
Finally, recent studies suggest that proteins important for mGlu5 function are lost and that mGlu5 signaling is impaired in tissues from AD patients and some preclinical animal models of AD.
Taken together, these studies raise the exciting possibility that mGlu5 PAMs may offer an exciting new therapeutic strategy to enhance cognitive function in patients suffering from AD and other age-related cognitive deficits. CK-p25 mice were maintained on doxycycline diet for 6 weeks following birth to maintain normal p25 levels in the forebrain during development.
Subsequently, CK-p25 mice were switched to normal chow to allow p25 induction for 6 weeks. A subset of littermate control mice were maintained continually on doxycycline diet throughout the studies to inhibit p25 overexpression.
At 12 weeks of age, mice underwent electrophysiology studies assessing hippocampal synaptic plasticity at the SC-CA1 synapse or behavioral studies evaluating cognitive function in the presence or absence of mGlu5 PAMs.
Hippocampal long term potentiation LTP is a form of synaptic plasticity essential for learning and memory. In addition, profound hippocampal- and cortical-mediated cognitive deficits were observed in these mice. Moreover, mGlu5 PAMs demonstrated dose-dependent reversal of cognitive deficits in contextual fear conditioning, novel object recognition task, as well as the pairwise discrimination task using touch screen technology in the CK-p25 mouse model of AD.
Utilizing the CK-p25 mouse model of AD, these studies demonstrate that selective potentiation of mGlu5 can reverse not only deficits in hippocampal neurotransmission but also severe cognitive deficits.
These results provide critical data in validating the potential utility of mGlu5 PAMs as a novel therapeutic approach for treatment of cognitive impairments associated with AD and other neurodegenerative disorders.
Serotonin has long been thought to be involved in a variety of behaviors, however given the complexity of this system, it has been difficult to clearly delineate the circuits involved in various aspects of behavior.
This is critical, as understand the circuits involved in the aversive actions of 5HT can lead to more effective drug treatment. Genetically modified mice were used in combination with a variety of cutting edge tools to probe 5HT circuits in the brain. Using in vivo recordings during fear conditioning, we found that fluoxetine exposure during fear learning lead to alterations in neuronal firing in the BNST.
We next explored the impact of both optically evoked and bath applied 5HT on BNST neurons in a ex vivo slice preparation. Interestingly, we found that 5HT lead to recruitment of a local inhibitory circuit that suppressed outputs to both the hypothalamus and the ventral tegmental area.
We then performed a series of in vivo experiments using chemogenetic and optogenetic approaches to demonstrate that this circuit is required for 5HT induced aversion. These results define the circuitry required for acute SSRI induced potentiation of fear. Moreover, we provide a pharmacological mechanism for mitigating this effect, suggesting new treatment modalities to minimize side effects of SSRI. Stress-related psychiatric disorders, such as post-traumatic stress disorder and major depression, occur twice as frequently in women as men.
Corticotropin-releasing factor CRF orchestrates the stress response and is hypersecreted in these disorders. Thus, sex differences in responses to CRF could contribute to the sex bias in disease prevalence.
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We previously identified sex differences in CRF1 receptor signaling and trafficking in the locus coeruleus LC that render LC neuronal responses to CRF greater in female than male rodents. However, the extent of sex differences in CRF sensitivity has not been systematically explored. Here we begin to address this question by examining how the central administration of CRF differentially activates stress-related brain regions in adult male and female rats.
Adult male and female Sprague-Dawley rats were surgically implanted with cannulas aimed at the lateral ventricle and allowed at least one week to recover during which vaginal cytology was collected to identify estrous cycle stage in females. Either vehicle artificial cerebral spinal fluid or ovine CRF 0.
One hour later, tissue was collected and processed using standard immunohistochemical approaches to visualize the immediate early gene, cFOS. ANOVAs were used to reveal the effects of infusion and hormonal condition on the number of cFOS positive profiles in select brain regions.
Surprisingly, in several brain regions, cFOS activation was altered in different estrous cycle phases in females and, in particular, diestrus females were distinguished from other groups. Collectively, these findings indicate that central CRF administration activates different circuits in males and females, and that differences are further revealed across the female estrous cycle.
Surprisingly, although cFOS has been widely used, previous studies were almost exclusively conducted with male rats. Thus, sex differences in the activation of brain circuits by stressors, neuropeptides, and other stimuli, may be an important, but underexplored, determinant of sex differences in behavior and perhaps even pathology. However, studies in humans have exclusively examined the effects of THC on responding to discrete fear cues i. This question of specificity is important, especially in light of evidence suggesting that animals, including humans, rely heavily on context when appraising potential sources of danger.
The current study examined the effects of THC on brain i. Forty healthy adult volunteers completed four experimental sessions over the course of 10 days. Self-reported expectancy of the unconditioned stimulus i. There were no effects of drug on US expectancy ratings.
For the visual-spatial context, however, there was a main effect of session and a main effect of drug on bilateral hippocampal activation that was qualified by a significant drug x session interaction relatively specific to the hippocampus right: This adds to a growing literature implicating the hippocampus in contextual memory processes and more importantly could suggest that THC, and potentially other CB1 agonists, facilitates and sustains the appraisal and recognition of safe environments via enhancement of hippocampal engagement.
This mechanism holds promise for the treatment of individuals with anxiety and stress-related disorders as CB1 agonists may prove to be a useful cognitive enhancer adjunct to behavioral therapies that rely on extinction learning to effectively discriminate danger from safety and its retention across contexts.
Epidemiological data suggest that body mass index and obesity are strong risk factors for depression and anxiety. In rodents, diet-induced obesity produces depression-like behaviors in the forced swim, and sucrose preference tests, but the mechanism underlying this effect is poorly understood.
Alterations in glutamatergic prefrontal cortical and amygdalar inputs to the nucleus accumbens NAc are thought to contribute to depression and anxiety.
Furthermore, obesity is accompanied by elevations in circulating insulin, and insulin receptor activation decreases excitatory glutamatergic transmission in the hippocampus and the ventral tegmental area. However, no studies have examined the effect of insulin or the development of insulin resistance on NAc glutamatergic transmission, nor has the role of insulin-resistance in anxiety or depression been examined.
Thus, we have begun a series of experiments to determine whether NAc glutamatergic transmission is affected by insulin, and to determine whether development of insulin-resistance contributes to depression- and anxiety-like behaviors.
The contribution of insulin receptors and insulin-like growth factor receptors IGFR to insulin's effects on EPSCs were determined using pharmacological approaches.
For behavioral studies, male and female selectively bred obesity-prone and obesity-resistant rats were used.
Food intake and weight gain were monitored throughout. Depressive-like behaviors were evaluated using the forced swim test at two different water depths after spontaneous weight gain in obesity-prone rats. Fasted plasma levels of insulin were used to determine metabolic dysfunction and body composition was determined using NMR.
This effect was completely reversed after insulin wash out. Furthermore, insulin produced a marked reduction in sEPCS frequency, suggesting that its effects are mediated by reducing presynaptic glutamate release.
In addition, when the IGFR antagonist picropodophyllotoxin 0. This suggests that reductions in glutamatergic transmission induced by insulin are mediated by the IGFR and that insulin receptor activation may produce opposing effects on excitatory transmission in the NAc.
Ongoing studies are examining these effects of insulin after diet-induced obesity and the development of insulin resistance. In behavioral studies, obesity-prone rats gained substantially more weight and fat mass than obesity-resistant rats when maintained on standard lab chow, as expected. Anxiety-like behaviors in the elevated plus maze and open field tests were enhanced in obese male and female rats.
Furthermore, the magnitude of these anxiety-like behaviors was positively correlated with weight gain.
No pronounced differences in depressive-like behaviors were found between groups. Preliminary results suggest that diet-induced obesity may enhance anxiety-like behaviors even in obesity-resistant rats. Current results suggest that insulin bi-directionally influences glutamatergic transmission in the NAc, with IGFR activation producing reductions in excitatory transmission and insulin receptor activation producing increases.
These effects of insulin were reversed by insulin wash out, suggesting that insulin can dynamically regulate excitatory transmission in the NAc. This is in contrast to the VTA where insulin produces longer lasting reductions in excitatory transmission. Anxiety-like behaviors increased with the development of obesity in obesity-prone and obesity-resistant rats. Ongoing studies are examining the relationship between insulin-resistance and enhanced anxiety. Obsessive-compulsive disorder OCD is treated with exposure with response prevention ERP therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions.
Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions.
An animal model of ERP would be useful for understanding neural mechanisms. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacological inactivation of lateral orbitofrontal cortex lOFC or DBS of the ventral striatum reduced persistent avoidance.
This rodent model may be useful for understanding the neurobiological mechanisms of ERP therapy. Anxious temperament AT during childhood is a risk factor for the later development of anxiety, depression, and comorbid substance abuse disorders.
Children with an extremely anxious temperament ATreact to novelty with increased behavioral inhibition and increased levels of physiological arousal. Our group has extensively validated a nonhuman primate model of early-life AT. We found that AT is stable over time, across contexts, and predicts inhibited social behavior naturalistic settings.
Here, we combined RNA sequencing of targeted brain tissue, with brain imaging and behavioral assessments to investigate the molecular underpinnings of AT in the primate. The non-human primate is an ideal model to investigate the molecular underpinnings of AT, because it allows researchers to leverage techniques that are possible in rodents alongside techniques that are more commonly used in humans.
Our large-scale FDG-PET imaging studies of young rhesus monkeys revealed a brain-wide network of regions to be associated with AT, which include the central nucleus of the amygdala Ce.
The Ce is of particular interest because mechanistic studies demonstrate that damage to the Ce is sufficient to decrease the expression of AT. Moreover, as part of the extended amygdala, the Ce is connected, directly and indirectly, with regulatory and evaluative cortical regions, as well as the regions required to initiate defensive behavioral and physiological responses. Gene expression is an ideal method for examining the molecular underpinnings of AT because it reflects the combination of genetic and environmental influences that underlie an anxious brain.
We examined Ce gene expression using RNA-seq in combination with assessments of behavior, physiology, and multi-modal brain imaging. AT was assessed in response to the potentially threatening no-eye-contact NEC condition of the human intruder paradigm, using a composite of increased behavioral inhibition, decreased vocalizations, and increased cortisol. Using regression techniques, we examined variation in Ce mRNA expression in relation to individual differences in AT, as well as structural and functional imaging measures.
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Building on our previous work, in this study we examined transcript features, such as exons, introns, and splice junctions in relation to AT.
To optimize the reliability of our analyses, initial analyses were restricted to features where we mapped an average of at least 50 reads with at least one read in each animal. These features represent different genes, where expression of all or part of the transcript was associated with individual differences in AT.
Consistent with our prior work suggesting an important role for Ce neuroplasticity in AT, AT-related transcripts encoded molecules involved in mechanisms associated with neuroplasticity and synaptic restructuring e.
Interestingly, additional analyses revealed differential relationships between the levels of these transcripts and metabolism throughout the AT-neural network. Understanding the molecular functions that give rise to heightened dispositional anxiety is an important step toward developing novel behavioral and pharmacological treatments for early-life anxiety.
In particular, insights into the Ce molecules that give rise to dispositional anxiety and its associated brain alterations will provide novel information about both the cellular composition and behavior of neurons within the Ce of highly anxious individuals. The current data provide evidence for novel mechanisms underlying neuroplastic processes within the Ce that may mediate the early-life risk to develop anxiety, depression, and comorbid substance abuse disorders.
A refined understanding of these mechanisms will provide a framework for developing novel treatments aimed at preventing children with an extreme dispositional anxiety from the life-long suffering that is associated with stress-related psychopathology.
The dorsal anterior cingulate cortex dACC and bilateral anterior insula aIrepresent a key nodes within a salience network that activates in response to cognitively relevant events e. At present, however, it remains unknown whether atypical interaction between salience and default mode networks represents a marker for pathology e. To address this gap in knowledge, we tested the relationship of OCD symptom severity with connectivity between salience network and vmPFC.
We reasoned that a pathologic role would be supported if OCD severity was positively associated with atypical salience network-vmPFC interactions, whereas a compensatory role would be supported if atypical connectivity and OCD severity were negatively associated. Functional magnetic resonance imaging fMRI data was collected in 69 patients with pediatric Correct incongruent and correct congruent trials were contrasted to derive functionally defined seeds in dACC 12 mm sphere centered at -3, 8, 49 and bilateral aI 12 mm spheres centered at 45, 17, -5 on right,17, 4 on left.
To examine intrinsic functional connectivity, the time series from these seeds were extracted from a general linear model that regressed out task condition, yielding a residual time series used as a covariate as well as movement parameters and age in a separate model that again included all task event regressors to examine positive and negative correlations between seed regions and other voxels in the brain. These correlations are described as intrinsic connectivity because this method identifies interregional coupling that is independent of and linearly superimposed upon event-related activity.
Consistent with prior literature, positive connectivity maps for dACC and bilateral aI seeds defined the salience network, whereas negative connectivity maps showed anti-correlations between these seeds with vmPFC and posterior cingulate cortex i. There were no other inverse and no positive associations of OCD severity and SN seed connectivity with vmPFC or any other default mode network region e. Pediatric OCD has been previously characterized by atypical interactions between the salience and default mode networks.
In this sample, greater connectivity of salience network, particularly the bilateral aI, with the vmPFC default mode region was associated with lower OCD symptom severity. This finding suggests that atypical aI-vmPFC connectivity in OCD may enable young patients to more effectively resist obsessive thoughts and compulsive urges.
Studies of young patients before and after treatment are needed to establish whether increases in salience-default mode network connectivity drive reduction in symptom severity. Few studies have examined potential differences between social anxiety disorder SAD and generalized anxiety disorder GAD in the sensitivity to detect emotional expressions. The task presented faces expressing increasing degrees of emotional intensity, slowly changing from a neutral to a full-intensity happy 20 trialssad 20 trialsor angry 20 trials expression Niedenthal, et al.
Participants are instructed to use a slide bar to view the movie frames from left to right, and to stop at the first frame where they perceive an emotion. The frame selected thus indicates the intensity of emotion required to identify the facial expression. We conducted a mixed-model repeated measures ANOVA, with expression angry, happy, sad as the repeated measure, diagnosis as the between subjects factor, and the frame at which the movie was stopped as the dependent variable.
Bonferroni post-hoc tests revealed that all groups required the smaller number of frames to detect happy expressions, followed by angry expressions, and the greatest number of frames to detect for sad expressions. The list features less than 5 percent of the lawyers in the Commonwealth of Pennsylvania each year. She is based in Atlanta and available worldwide to serve as a mediator, arbitrator, special master and discovery referee in areas including intellectual property, copyright, patent and trademark infringement, trade secrets and related disputes involving contracts and licenses.
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Mastering the Language of Swashbucklers and Rogues. His bio from a Kenyon Review story sums up his work. Deputy Attorney General Larry Thompson.
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I like the people here … because they are smart. They do great work. Dennis Fletcher Jones Sr. Fenster represents employers in class and collective action lawsuits regarding pay disputes. In addition to litigating wage and hour lawsuits, from single-plaintiff cases to complex, large-scale collective actions, Fenster counsels employers on legal compliance issues including employee classification issues, workplace policies, and pay practices. Labovitz 74L chairs Council for Quality Growth Monday, May 7, Steve Labovitz 74L has been named chair of the Council for Quality Growth, the largest trade organization in Georgia, which concentrates on smart growth, development and infrastructure improvements in the metro Atlanta area and Georgia.
His practice there focuses on complex business litigation and appeals. Chakravarty, the federal prosecutor who prosecuted the Boston Marathon bombing case, joins the firm as a partner and will practice in its White Collar Defense and Investigations group and the Cybersecurity, Data Protection and Privacy practice.
Chakravarty arrives from the U. Department of Justice where he prosecuted the U. He led the crisis response and investigation team minutes after the bombing, developed and presented the case at grand jury, trial and sentencing, and assisted in the appeal. Read the firm release.
Mangiafico Saturday, March 3, Edgar S. Taylor 66Ox 68C 71L passed away on April 22, A litigator with a long list of storied clients, Taylor at one point argued at the U. Supreme Court, a case that involved tax law and alcohol regulations.