Hagit Cohen

Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood

Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.

Autonomic dysfunction in patients with fibromyalgia: application of power spectral analysis of heart rate variability.

OBJECTIVES To assess the interaction between the sympathetic and parasympathetic systems in patients with fibromyalgia syndrome (FM), using power spectrum analysis (PSA) of heart rate variability (HRV). In addition, we explored the association between HRV, measures of tenderness, FM symptoms, physical function, psychological well being and quality of life. METHODS We studied 22 women with FM and 22 age-matched healthy women. Twenty-minute electrocardiogram recordings were obtained in a supine position during complete rest. Spectral analysis of R-R intervals was done by the fast-Fourier transform algorithm. RESULTS Heart rate was significantly higher in FM patients compared with controls (P < .006). FM patients had significantly lower HRV compared with controls (P= .001), and higher low-frequency (LF) and lower high-frequency (HF) components of PSA than controls (P < .001). Quality of life, physical function, anxiety, depression, and perceived stress were moderately to highly correlated with LF, HF (in normalized units), and LF/HF. No association was observed between HRV parameters and measures of tenderness and FM symptoms. CONCLUSIONS The basal autonomic state of patients with FM is characterized by increased sympathetic and decreased parasympathetic tones. Autonomic dysregulation may have implications regarding the symptomatology, physical and psychological aspects of health status.

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.

Setting apart the affected: The use of behavioral criteria in animal models of post traumatic stress disorder

Post-traumatic stress disorder (PTSD) affects about 20–30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteria—CBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.

Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects

Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies.1,2 More recently, several candidate genes have been investigated for their possible role in alcoholism3–6 and cocaine abuse.7 Specific genetic factors in opioid substance abuse have not been investigated in man, although animal studies suggest that quantitative trait loci (QTLs) can be identified that predispose mice both to morphine and alcohol preference.8 Central dopaminergic pathways figure prominently in drug-mediated reinforcement9 suggesting that dopamine receptors are likely candidates for association with substance abuse in man. In addition, we recently reported an association between a human personality trait, Novelty Seeking10–12 and the long alleles (represented chiefly by the 7-repeat) of the D4 dopamine receptor (D4DR) exon III polymorphism. The personality trait of Novelty Seeking is also more pronounced in substance abusers, who score higher in this dimension than control subjects.13 The twin role of dopamine receptors in mediating Novelty Seeking10–12 and drug-reinforcement9 prompted us to examine a group of Israeli heroin addicts for prevalence of the D4DR repeat polymorphism. We now show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46. To our knowledge this is the first report of an association between a specific genetic polymorphism and opioid addiction.

An Animal Model of Posttraumatic Stress Disorder: The Use of Cut‐Off Behavioral Criteria

Abstract: Considerable heterogeneity exists in the response of human subjects exposed to extreme traumatizing events. Posttraumatic stress disorder (PTSD) is diagnosed in 20‐30% of those exposed. Clinical studies of this population employ stringent inclusion/exclusion criteria, yet animal studies have routinely included the entire exposed population as the study population. We examined the effect of grouping stressed rats according to the magnitude of their response on the statistical analysis of behavioral models. Exposure to a predator stimulus was used as the stress paradigm. Response magnitude was assessed in two consecutive behavioral tests measuring anxiety‐ and stress‐related behaviors and was used to divide the animals into groups. The two extremes were studied, that is, those clearly “maladapted” and those clearly “well‐adapted,” using arbitrarily selected severity‐measures, the “cut‐off behavioral criteria” (CBC). Data for the partially affected middle group were discarded for reasons of clarity. The hypothalamic‐pituitary‐adrenal axis and heart rate variability were analyzed for the entire exposed population and then reexamined according to the CBCs. When the CBCs were applied, we found PTSD‐like symptoms in only 22.0% of exposed rats. Compared to controls and to well‐adapted exposed rats, the behaviorally maladapted rats displayed disordered physiological measures. They had significantly higher plasma corticosterone and ACTH levels, increased sympathetic activity, diminished vagal tone, and increased sympathovagal balance. These differences surfaced only when data were analyzed according to the CBCs. Animals respond to stress heterogeneously, resembling humans. Overlooking heterogeneity in responses obscures the results of biobehavioral data analysis. We submit that animals exposed to trauma should be divided into groups according to the magnitude of their response and be studied accordingly.

Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity.

Although aggressive, violent, and dangerous behavior in man has multifactorial causes, genetic factors are estimated by twin and adoption studies to substantially contribute to the development of such conduct. Recently, homozygosity of a low enzyme activity variant of the catechol O-methyltransferase (COMT) gene was reported to be associated with aggressive behavior in a group of schizophrenic patients. We observe a similar tendency in a group of 30 schizophrenic patients who were confined to a maximum-security psychiatric facility for homicide. Significant excess (46.7% versus 21.0%) homozygosity of the low activity COMTmet/met genotype was observed in 30 mostly male (28 of 30) homicidal schizophrenic patients compared with 415 control subjects (Pearson chi(2) = 10.53, P = 0.005, df = 2). No difference in COMT genotype was found between 62 nonviolent schizophrenic patients and the 415 control subjects (chi(2) = 0.963, P > 0.1, df = 2). A trend for excess (46.7% versus 25.8%) homozygosity of the low activity COMTmet/met genotype was also observed when the homicidal schizophrenic subjects were compared directly with the nonviolent schizophrenic patients (chi(2) = 4.03, P = 0.1, df = 2). Similarly, an excess of the low activity COMTmet allele was observed in homicidal versus nonviolent schizophrenic patients (chi(2) = 2.92, P = 0.087, df = 2). Similar results were obtained if only male subjects were examined. No significant difference was found between control (257 Ashkenazi and 152 non-Ashkenazi Jews) COMT genotypes in the two principal ethnic groups examined (chi(2) = 3.79, P > 0.1, df = 2). Finally, no association was observed between homicidal behavior in schizophrenic patients and the dopamine D4 exon III repeat length polymorphism (D4DR) and the serotonin transporter promoter-region polymorphism (5-HTTLPR). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:628-633, 1999.

The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.

IFN-γ enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease

The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin‐6 and tumor necrosis factor‐α, the adaptive immunity cytokine IFN‐γ enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN‐γ is more pronounced in both wild‐type mice and mice with Alzheimers‐like disease and is associated with neuroprotection. In addition, IFN‐γ reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimers disease. We demonstrate that limited amounts of IFN‐γ in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.—Baron, R., Nemirovsky, A., Harpaz, I., Cohen, H., Owens, T., Monsonego, A. IFN‐γ enhances neurogenesis in wild‐type mice and in a mouse model of Alzheimers disease. FASEB J. 22, 2843–2852 (2008)

Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study

BACKGROUND Transcranial magnetic stimulation (TMS) has become, over the last few years, a promising avenue for new research in affective disorders. In this study we have evaluated the clinical effect of slow TMS on posttraumatic stress disorder (PTSD) symptoms. METHODS Ten PTSD patients were given one session of slow TMS with 30 pulses of 1 m/sec each, 15 to each side of the motor cortex. RESULTS Symptoms of PTSD were assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the effect was rather short and transient. CONCLUSIONS The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for PTSD patients.