Faculty Bibliography

Glucocorticoids, released in high concentrations from the adrenal cortex during stressful experiences, bind to glucocorticoid receptors in nuclear and peri-nuclear sites in neuronal somata. Their classically known mode of action is to induce gene promoter receptors to alter gene transcription. Nuclear glucocorticoid receptors are particularly dense in brain regions crucial for memory, including memory of stressful experiences, such as the hippocampus and amygdala. While it has been proposed that glucocorticoids may also act via membrane bound receptors, the existence of the latter remains controversial. Using electron microscopy, we found glucocorticoid receptors localized to non-genomic sites in rat lateral amygdala, glia processes, presynaptic terminals, neuronal dendrites, and dendritic spines including spine organelles and postsynaptic membrane densities. The lateral nucleus of the amygdala is a region specifically implicated in the formation of memories for stressful experiences. These newly observed glucocorticoid receptor immunoreactive sites were in addition to glucocorticoid receptor immunoreactive signals observed using electron and confocal microscopy in lateral amygdala principal neuron and GABA neuron soma and nuclei, cellular domains traditionally associated with glucocorticoid immunoreactivity. In lateral amygdala, glucocorticoid receptors are thus also localized to non-nuclear-membrane translocation sites, particularly dendritic spines, where they show an affinity for postsynaptic membrane densities, and may have a specialized role in modulating synaptic transmission plasticity related to fear and emotional memory

The amygdala is critical for acquiring and expressing conditioned fear responses elicited by sensory stimuli that predict future punishment, but there is conflicting evidence about whether the amygdala is necessary for perceiving the aversive qualities of painful or noxious stimuli that inflict primary punishment. To investigate this question, rats were fear conditioned by pairing a sequence of auditory pips (the conditioned stimulus, or CS) with a brief train of shocks to one eyelid (the unconditioned stimulus, or US). Conditioned responding to the CS was assessed by measuring freezing responses during a test session conducted 24 h after training, and unconditioned responding to the US was assessed by measuring head movements evoked by the eyelid shocks during training. We found that pre-training electrolytic lesions of the amygdala's lateral (LA) nucleus blocked acquisition of conditioned freezing to the CS, and also significantly attenuated unconditioned head movements evoked by the US. Similarly, bilateral inactivation of the amygdala with the GABA-A agonist muscimol impaired acquisition of CS-evoked freezing, and also attenuated US-evoked responses during training. However, when amygdala synaptic plasticity was blocked by infusion of the NR2B receptor antagonist ifenprodil, acquisition of conditioned freezing was impaired but shock reactivity was unaffected. These findings indicate that neural activity within the amygdala is important for both predicting and perceiving the aversive qualities of noxious stimuli, and that synaptic plasticity within LA is the mechanism by which the CS becomes associated with the US during fear conditioning

We sought to determine whether contextual fear conditioning, a hippocampal-dependent task, would affect neurogenesis in the dentate gyrus of the hippocampus, and if so, to identify which aspect of the training experience accounts for the change. The immediate shock deficit paradigm was used, together with bromodeoxyuridine immunohistochemistry, to isolate the contribution of different aspects of contextual fear conditioning to neurogenesis. Contextual fear learning caused a 33% decrease in the number of proliferating cells that was anatomically restricted to the dentate gyrus with no change in cell survival or differentiation. This attenuation was not related to exposure to the conditioned stimulus alone, the footshock unconditioned stimulus alone, or the expression of fear to the context after training. Instead, the effect of context conditioning on cell proliferation appears to be specifically due to the formation of an association between the context and shock during training, an amygdala dependent function

Fear and anxiety represent emotions that have captured the minds of the public for as long as artists and philosophers have been commenting on the most troubling problems confronting human beings. No doubt, this fascination relates to the ubiquity of anxiety and the great toll that it takes on many individuals: As any person who has experienced the grip of anxiety firsthand can attest, anxiety disorders bring a level of suffering that warrants considerable attention from both a clinical and research perspective. Four major insights have crystallized in recent research on pediatric anxiety disorders, each of which is echoed in papers within this special section. Two papers in the special section address issues relevant to risk for anxiety. While each of the seven papers in this special section illustrates the diversity of research conducted during the past decade, these reports clearly raise as many questions as they answer. One can only hope that studies over the next 10 years, by capitalizing on methodological advances allowing us to assess functional aspects of the human fear circuit, will address the many pressing questions raised by studies conducted over the prior 10 years.

The stimulants have been the mainstay of pharmacologic treatment for over fifty years. Methylphenidate is the most frequently prescribed of the stimulant agents. In the past, one of the main drawbacks of these agents was the abbreviated duration of action. Over the last few years three longer acting methylphenidate preparations have been released to the market. Though all these agents contain the same chemical compound they do vary in a number of ways. In this article we will present how the formulations compare in their technology and the differences in their delivery systems. We will also compare the available literature that focus on head to head comparisons in terms of pharmacokinetics studies and those reports that present efficacy data. Finally, we will suggest based on a theoretical framework on how to approach selecting an agent based on the results of these trials and the individual needs of the patient

In a multisite study of 351 children with autism spectrum disorders, 21 children with developmental delays, and 31 children with typical development, this study used caregiver interviews (i.e., the Autism Diagnostic Interview-Revised) at the time of entry into other research projects and follow-up telephone interviews designed for this project to describe the children's early acquisition and loss of social-communication milestones. Children who had used words spontaneously and meaningfully and then stopped talking were described by their caregivers as showing more gestures, greater participation in social games, and better receptive language before the loss and fewer of these skills after the loss than other children with autism spectrum disorders. A significant minority of children with autism without word loss showed a very similar pattern of loss of social-communication skills, a pattern not observed in the children with developmental delays or typical development

OBJECTIVE: Heart rate variability (HRV) reflects functioning of the autonomic nervous system and possibly also regulation by the neural limbic system, abnormalities of which have both figured prominently in various etiological models of schizophrenia, particularly those that address patients' vulnerability to stress in connection to psychosis onset and exacerbation. This study provides data on cardiac functioning in a sample of schizophrenia patients that were either medication free or on atypical antipsychotics, as well as cardiac data on matched healthy controls. We included a medication-free group to investigate whether abnormalities in HRV previously reported in the literature and associated with atypical antipsychotics were solely the effect of medications or whether they might be a feature of the illness (or psychosis) itself. METHOD: We collected 24-hour ECGs on 19 patients and 24 controls. Of the patients, 9 were medication free and 10 were on atypical antipsychotics. All subject groups were matched for age and gender. Patient groups showed equivalent symptom severity and type, as well as duration of illness. We analyzed the data using nonlinear complexity (symbolic dynamic) HRV analyses as well as standard and relative spectral analyses. RESULTS: For the medication-free patients as compared to the healthy controls, our data show decreased R-R intervals during sleep, and abnormal suppression of all frequency ranges, but particularly the low frequency range, which persisted even after adjusting the spectral data for the mean R-R interval. This effect was exacerbated for patients on atypical antipsychotics. Likewise, nonlinear complexity analysis showed significantly impaired HRV for medication-free patients that was exacerbated in the patients on atypical antipsychotics. CONCLUSIONS: Altogether, the data suggest a pattern of significantly decreased cardiac vagal function of patients with schizophrenia as compared to healthy controls, apart from and beyond any differences due to medication side effects. The data additionally confirm earlier reports of a deleterious effect of atypical antipsychotics on HRV, which may exacerbate an underlying vulnerability in patients. These results support previous evidence that autonomic abnormalities may be a core feature of the illness (or psychosis), and that an even more conservative approach to cardiac risk in schizophrenia than previously thought may therefore be clinically appropriate