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1.  Hippocampal Dysfunction Effects on Context Memory: Possible Etiology for Post-traumatic Stress Disorder 
Neuropharmacology  2011;62(2):674-685.
Hippocampal volume reductions and functional impairments are reliable findings in post-traumatic stress disorder (PTSD) imaging studies. However, it is not clear if and how hippocampal dysfunction contributes to the etiology and maintenance of PTSD. Individuals with PTSD are often described as showing fear responses to trauma reminders outside of contexts in which these cues would reasonably predict danger. Animal studies suggest that the hippocampus is required to form and recall associations between contextual stimuli and aversive events. For example, the hippocampus is critical for encoding memories in which a complex configuration of multiple cues is associated with the aversive event. Conversely, the hippocampus is not required for associations with discrete cues. In animal studies, if configural memory is disrupted, learning strategies using discrete cue associations predominate. These data suggest poor hippocampal function could bias the organism towards forming multiple simple cue associations during trauma, thus increasing the chances of fear responses in multiple environments (or contexts) in which these cues may be present. Here we will examine clinical and animal literature to support a theory of hippocampal dysfunction as a primary contributory factor to the etiology of PTSD, and discuss future research required to test these hypotheses.
PMCID: PMC3175276  PMID: 21596050
2.  Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice 
Brain research  2010;1368:65-70.
Unregulated production of reactive oxygen species (ROS) is a marker of cellular and organismal aging linked to cognitive decline in humans and rodents. The sources of elevated ROS contributing to cognitive decline are unknown. Because NADPH oxidase (Nox) inhibition may prevent memory decline with age, we hypothesized that Nox and not mitochondrial sources of synaptic ROS production are linked to individual variance in cognitive performance in aged mice. Young (8 mo) and aged (26 mo) mice were tested in the novel object recognition task (NORT). Mitochondrial and Nox ROS production was assayed in isolated synaptosomes using spin-trapping electron paramagnetic resonance (EPR) spectroscopy. Aged mice exhibited variance in NORT performance, with some performing similar to young mice while others exhibited poorer short-term memory. EPR studies indicated that Nox rather than mitochondria was the major ROS source at the synapse, and Nox- but not mitochondrial-induced ROS levels correlated with NORT performance in aged mice. Our findings support the hypothesis that variance in Nox-specific synaptic ROS production may predict short-term memory deficits with age.
PMCID: PMC3018762  PMID: 21075081
aging; short-term memory; superoxide; NADPH oxidase; mitochondria; synaptosomes
3.  Predictors of Risk and Resilience for Posttraumatic Stress Disorder Among Ground Combat Marines: Methods of the Marine Resiliency Study 
The Marine Resiliency Study (MRS) is a prospective study of factors predictive of posttraumatic stress disorder (PTSD) among approximately 2,600 Marines in 4 battalions deployed to Iraq or Afghanistan. We describe the MRS design and predeployment participant characteristics. Starting in 2008, our research team conducted structured clinical interviews on Marine bases and collected data 4 times: at predeployment and at 1 week, 3 months, and 6 months postdeployment. Integrated with these data are medical and career histories from the Career History Archival Medical and Personnel System (CHAMPS) database. The CHAMPS database showed that 7.4% of the Marines enrolled in MRS had at least 1 mental health diagnosis. Of enrolled Marines, approximately half (51.3%) had prior deployments. We found a moderate positive relationship between deployment history and PTSD prevalence in these baseline data.
PMCID: PMC3431952  PMID: 22575082
4.  The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice 
Neuropharmacology  2012;63(3):480-485.
Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a “Low” or “High” gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the “low gating” group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.
PMCID: PMC3572212  PMID: 22575075
Schizophrenia; Pre-pulse inhibition; Glutamate; Pregabalin; Startle; Sensorimotor gating
5.  Voxel-wise resting-state MEG source magnitude imaging study reveals neurocircuitry abnormality in active-duty service members and veterans with PTSD 
NeuroImage : Clinical  2014;5:408-419.
Post-traumatic stress disorder (PTSD) is a leading cause of sustained impairment, distress, and poor quality of life in military personnel, veterans, and civilians. Indirect functional neuroimaging studies using PET or fMRI with fear-related stimuli support a PTSD neurocircuitry model that includes amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC). However, it is not clear if this model can fully account for PTSD abnormalities detected directly by electromagnetic-based source imaging techniques in resting-state. The present study examined resting-state magnetoencephalography (MEG) signals in 25 active-duty service members and veterans with PTSD and 30 healthy volunteers. In contrast to the healthy volunteers, individuals with PTSD showed: 1) hyperactivity from amygdala, hippocampus, posterolateral orbitofrontal cortex (OFC), dorsomedial prefrontal cortex (dmPFC), and insular cortex in high-frequency (i.e., beta, gamma, and high-gamma) bands; 2) hypoactivity from vmPFC, Frontal Pole (FP), and dorsolateral prefrontal cortex (dlPFC) in high-frequency bands; 3) extensive hypoactivity from dlPFC, FP, anterior temporal lobes, precuneous cortex, and sensorimotor cortex in alpha and low-frequency bands; and 4) in individuals with PTSD, MEG activity in the left amygdala and posterolateral OFC correlated positively with PTSD symptom scores, whereas MEG activity in vmPFC and precuneous correlated negatively with symptom score. The present study showed that MEG source imaging technique revealed new abnormalities in the resting-state electromagnetic signals from the PTSD neurocircuitry. Particularly, posterolateral OFC and precuneous may play important roles in the PTSD neurocircuitry model.
•Resting-state MEG detects abnormal electromagnetic activity in PTSD neurocircuitry•PTSD showed hyperactivity in amygdala, hippocampus, and orbitofrontal cortex•PTSD showed hypoactivity in vmPFC, frontal pole, and dlPFC•PTSD symptom score correlated with MEG activity
PMCID: PMC4145534  PMID: 25180160
MEG; Post-traumatic stress disorder; Amygdala; Ventromedial prefrontal cortex; Orbitofrontal cortex; Precuneous
6.  Age-associated improvements in cross-modal prepulse inhibition in mice 
Behavioral neuroscience  2010;124(1):133-140.
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe pre-attentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.
PMCID: PMC3088993  PMID: 20141288
Prepulse Inhibition; aging; cross-modal; translational validity
7.  Isolation rearing induced deficits in contextual fear learning do not require CRF2 receptors 
Behavioural brain research  2010;209(1):80-84.
Post-weaning social isolation of rodents is used to model developmental stressors linked to neuropsychiatric disorders including schizophrenia as well as anxiety and mood disorders. Isolation rearing produces alterations in emotional memory and hippocampal neuropathology. Corticotropin releasing factor (CRF) signaling has recently been shown to be involved in behavioral effects of isolation rearing. Activation of the CRF2 receptor is linked to stress-induced alterations in fear learning and may also be involved in long term adaptation to stress. Here we tested the hypothesis that CRF2 contributes to isolation rearing effects on emotional memory. At weaning, mice were housed either in groups of 3 or individually in standard mouse cages. In adulthood, isolation-reared mice exhibited significant reductions in context-specific, but not cue-specific, freezing. Isolation reared mice exhibited no significant changes in locomotor exploration during brief exposure to a novel environment, suggesting that the reduced freezing in response to context cues was not due to activity confounds. Isolation rearing also disrupted context fear memory in mice with a CRF2 gene null mutation, indicating that the CRF2 receptor is not required for isolation effects on fear memory. Thus, isolation rearing disrupts hippocampal-dependent fear learning as indicated by consistent reductions in context-conditioned freezing in two separate cohorts of mice, and these effects are via a CRF2-independent mechanism. These findings may be clinically relevant because they suggest that isolation rearing in mice may be a useful model of developmental perturbations linked to disruptions in emotional memory in a variety of neuropsychiatric disorders.
PMCID: PMC2832092  PMID: 20097235
social isolation; fear conditioning; corticotropin releasing factor; emotional memory; locomotor activity; mice
8.  Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice 
Neuropharmacology  2013;70:156-167.
γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or the Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, however this effect may be attributable to analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice.
PMCID: PMC3644349  PMID: 23376712
GABAB receptor; positive allosteric modulator; anxiety; learning; memory
9.  Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury 
NeuroImage : Clinical  2014;5:109-119.
Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain tissues in mTBI patients generate abnormal slow-waves (1–4 Hz) that can be measured and localized by resting-state magnetoencephalography (MEG). In this study, we develop a voxel-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mTBI on a single-subject basis. A normative database of resting-state MEG source magnitude images (1–4 Hz) from 79 healthy control subjects was established for all brain voxels. The high-resolution MEG source magnitude images were obtained by our recent Fast-VESTAL method. In 84 mTBI patients with persistent post-concussive symptoms (36 from blasts, and 48 from non-blast causes), our method detected abnormalities at the positive detection rates of 84.5%, 86.1%, and 83.3% for the combined (blast-induced plus with non-blast causes), blast, and non-blast mTBI groups, respectively. We found that prefrontal, posterior parietal, inferior temporal, hippocampus, and cerebella areas were particularly vulnerable to head trauma. The result also showed that MEG slow-wave generation in prefrontal areas positively correlated with personality change, trouble concentrating, affective lability, and depression symptoms. Discussion is provided regarding the neuronal mechanisms of MEG slow-wave generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic transmission in TBI. This study provides an effective way for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI.
•A voxel-based whole-brain MEG slow-wave source imaging method for mild TBI.•The new approach showed 84.5% positive detection rate in 84 mild TBI patients.•The new approach detected loci of injury in mild TBI patients on a single-subject basis.•MEG slow-wave source imaging revealed brain areas vulnerable to mild TBI.•MEG slow-wave generations correlated with mild TBI symptoms.
PMCID: PMC4087185  PMID: 25009772
Magnetoencephalography; Traumatic brain injury; Slow-wave; Blast; Axonal injury
10.  5-HT1A receptor activation is necessary for 5-MeODMT-dependent potentiation of feeding inhibition 
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT1A receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT1A receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT1A receptor antagonist, WAY100635, reverses the 5-MeODMT-dependent potentiation of feeding inhibition. Our findings hint at a mechanistic role for increased 5-HT1A receptor activation in restricting-type AN. Further implications for the interplay between anxiety and feeding inhibition in AN are discussed.
PMCID: PMC2724836  PMID: 19490926
Serotonin; Anorexia; Feeding; Anxiety; Impulsivity; Novelty
11.  Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT1A receptor knockout mice: Implications for schizophrenia 
Neuropharmacology  2011;61(0):10.1016/j.neuropharm.2011.04.001.
Serotonin-1A (5-HT1A) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT1A receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT1A receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT1A receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D1 or D2 receptors which could explain the behavioural changes observed in 5-HT1A receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT1A receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain.
PMCID: PMC3866100  PMID: 21501627
Schizophrenia; 5-HT1A receptors; Serotonin; Dopamine; NMDA receptors; Hallucinogens
12.  Impaired Sensorimotor Gating in Unmedicated Adults with Obsessive–Compulsive Disorder 
Neuropsychopharmacology  2012;37(5):1216-1223.
Functional and structural imaging studies suggest that obsessive–compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.
PMCID: PMC3306882  PMID: 22218093
obsessive–compulsive disorder; prepulse inhibition; sensorimotor gating; serotonin reuptake inhibitors; acoustic startle; tic disorder; mood/anxiety; stress disorders; biological psychiatry; serotonin; psychopharmacology; obsessive–compulsive disorder (OCD); prepulse inhibition (PPI); sensorimotor gating; serotonin reuptake inhibitors (SRIs); acoustic startle; tic disorder
13.  Corticotropin-releasing factor and noradrenergic signaling exert reciprocal control over startle reactivity 
Corticotropin-releasing factor (CRF) and norepinephrine (NE) levels are altered in post-traumatic stress disorder and may be related to symptoms of hyperarousal, including exaggerated startle, in these patients. In animals, activation of both systems modulates anxiety behaviors including startle plasticity, however it is unknown if they exert their actions orthogonally or dependently. We tested the hypothesis that NE receptor activation is required for CRF effects on startle and that CRF1 receptor activation is required for NE effects on startle. The study examined the effects of: 1) α2 agonist clonidine (0.18 mg/kg, ip), α1 antagonist prazosin (0.8 mg/kg), and β1/2 antagonist propranolol (0.8, 8.0 mg/kg) pretreatment on oCRF- (0.6 nmol) induced increases in startle reactivity and PPI disruptions; 2) α2 antagonist atipamezole (1–30 mg/kg) and α1 agonist cirazoline (0.025–1.0 mg/kg) treatment on startle; 3) CRF1 antagonist (antalarmin, 14 mg/kg) pretreatment on atipamezole- (10.0 mg/kg) induced increases in startle. oCRF robustly increased startle and reduced PPI. Pretreatment with clonidine or prazosin, but not propranolol, blocked oCRF-induced increases in startle but had no effect on oCRF-induced disruptions in PPI. Atipamezole treatment increased startle, which was partially attenuated by CRF1 antagonist pretreatment. Cirazoline treatment did not increase startle. These findings suggest that CRF modulation of startle, but not PPI, requires activation of α1 adrenergic receptors, while CRF1 activation also contributes to NE modulation of startle. These data support a bi-directional model of CRF-NE modulation of stress responses and suggest that both systems must be activated to induce stress effects on startle reactivity.
PMCID: PMC3601827  PMID: 21205416
CRF; CRH (corticotropin-releasing hormone); Norepinephrine; Startle; PTSD
14.  Factor analysis of attentional set-shifting performance in young and aged mice 
Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs), extradimensional shifts (EDSs), and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging.
Young (4 months, n = 16) and aged (23 months, n = 18) C57BL/6N mice performed an attentional set-shifting task (ASST) that evaluates simple discrimination (SD), compound discrimination (CD), IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice.
The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings.
The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.
PMCID: PMC3174878  PMID: 21838910
15.  Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice 
Age  2011;34(2):305-316.
Constitutive macroautophagy involved in the turnover of defective long-lived proteins and organelles is crucial for neuronal homeostasis. We hypothesized that macroautophagic dysregulation in selective brain regions was associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice and employed immunohistochemistry to assess cellular distribution of proteins involved in the selective degradation of ubiquitinated proteins via macroautophagy. Values of the discrimination ratio (DR, a measure of short-term recognition memory performance) in aged mice were significantly lower than those in young mice (median, 0.54 vs. 0.67; p = 0.005, U test). Almost exclusively in aged mice, there were clusters of puncta immunoreactive for microtubule-associated protein 1 light chain 3 (LC3), ubiquitin- and LC3-binding protein p62, and ubiquitin in neuronal processes predominantly in the hippocampal formation, olfactory bulb/tubercle, and cerebellar cortex. The hippocampal burden of clustered puncta immunoreactive for LC3 and p62 exhibited inverse linear correlations with DR in aged mice (ρ = −0.48 and −0.55, p = 0.044 and 0.018, respectively, Spearman’s rank correlation). These findings suggest that increased accumulation of autophagosomes within neuronal processes in selective brain regions is characteristic of aging. The dysregulation of macroautophagy can adversely affect the turnover of aggregate-prone proteins and defective organelles, which may contribute to memory impairment in aged mice.
PMCID: PMC3312638  PMID: 21431350
Autophagy; Brain aging; MAP1LC3; Object recognition test; p62; Ubiquitin
16.  Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors 
Psychopharmacology  2008;201(1):55-66.
The hallucinogenic tea known as ayahuasca is made from a combination of psychoactive plants that contribute the active components N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT (5-MeO-DMT), as well as the monoamine oxidase (MAO) inhibitors (MAOIs) harmine and harmaline for oral activity.
The present study examined the effects of 5-MeO-DMT in combination with MAOIs in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration. Interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg) and the 5-HT2A antagonist MDL 11,939 (1.0 mg/kg) were also performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in MAOI-treated animals.
5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) decreased locomotor activity and investigatory behavior. In rats pretreated with a behaviorally inactive dose of harmaline (0.1 mg/kg), 1.0 mg/kg 5-MeO-DMT had biphasic effects on locomotor activity, initially reducing locomotion and then increasing activity as time progressed. The ability of harmaline to shift 5-MeO-DMT to a biphasic locomotor pattern was shared by the selective MAOA inhibitor clorgyline, whereas the selective MAOB inhibitor (−)-deprenyl was ineffective. The late hyperactivity induced by the combination of 1.0 mg/kg 5-MeO-DMT and 0.3 mg/kg clorgyline was blocked by pretreatment with MDL 11,939. Pretreatment with WAY-100635 failed to attenuate either the early hypoactivity or the late hyperactivity.
The ability of harmaline to modify the behavioral effects of 5-MeO-DMT is mediated by inhibition of MAOA. Further, 5-HT2A receptors are responsible for the late hyperactivity induced by 5-MeO-DMT in the presence of MAOA inhibitors.
PMCID: PMC2929165  PMID: 18604652
Ayahuasca; hallucinogen; serotonin; 5-methoxydimethyltryptamine; harmaline; MAOI
17.  CRF1 and CRF2 Receptors are Required for Potentiated Startle to Contextual but not Discrete Cues 
Corticotropin-releasing factor (CRF) peptides and their receptors have crucial roles in behavioral and endocrine responses to stress. Dysregulation of CRF signaling has been linked to post-traumatic stress disorder, which is associated with increased startle reactivity in response to threat. Thus, understanding the mechanisms underlying CRF regulation of startle may identify pathways involved in this disorder. Here, we tested the hypothesis that both CRF1 and CRF2 receptors contribute to fear-induced increases in startle. Startle responses of wild type (WT) and mice with null mutations (knockout, KO) for CRF1 or CRF2 receptor genes were measured immediately after footshock (shock sensitization) or in the presence of cues previously associated with footshock (ie fear-potentiated startle, FPS). WT mice exhibited robust increases in startle immediately after footshock, which was dependent upon contextual cues. This effect was completely absent in CRF1 KO mice, and significantly attenuated in CRF2 KO mice. In contrast, CRF1 and CRF2 KO mice exhibited normal potentiation of startle by discrete conditioned cues. Blockade of both receptors via CRF1 receptor antagonist treatment in CRF2 KO mice also had no effect on FPS. These results support an additive model of CRF1 and CRF2 receptor activation effects on potentiated startle. These data also indicate that both CRF receptor subtypes contribute to contextual fear but are not required for discrete cued fear effects on startle reactivity. Thus, we suggest that either CRF1 or CRF2 could contribute to the increased startle observed in anxiety disorders with CRF system abnormalities.
PMCID: PMC2900918  PMID: 19020499
CRF; startle; conditioned fear; PTSD; fear potentiated startle; context fear
18.  Posttraumatic Stress Disorder: Emerging Concepts of Pharmacotherapy 
Expert opinion on emerging drugs  2009;14(2):251-272.
Posttraumatic stress disorder (PTSD) can result from a traumatic experience that elicits emotions of fear, helpless or horror. Most individuals remain asymptomatic or symptoms quickly resolve, but in a minority intrusive imagery and nightmares, emotional numbing and avoidance, and hyperarousal persist for decades. PTSD is associated with psychiatric and medical co-morbidities, increased risk for suicide, and with poor social and occupational functioning. Psychotherapy and pharmacotherapy are common treatments. Whereas, research supports the efficacy of the cognitive behavioral psychotherapies, there is insufficient evidence to unequivocally support the efficacy of any specific pharmacotherapy. Proven effective pharmacologic agents are sorely needed to treat core and targeted PTSD symptoms, and for prevention. This review describes current and emerging pharmacotherapies that advance these goals.
PMCID: PMC2791537  PMID: 19453285
19.  The mouse attentional set-shifting task: A method for assaying successful cognitive aging? 
Humans exhibit considerable variance in cognitive decline with age, with some exhibiting little disruption while others become significantly impaired. In aged rodents, individual differences in spatial memory have been used to identify putative compensatory mechanisms underlying successful hippocampal aging. However, there are few parallel rodent models of cognitive decline in frontal cortex-mediated functions. We tested the hypothesis that, like aged humans, aged mice would exhibit greater variance in executive function measures compared to young mice. We examined the performance of young and aged C57BL/6N mice in the attentional set-shifting task. While young and old mice did not differ on trials to criterion performance, aged mice exhibited significantly greater variance in mean correct latency – selective to the extradimensional shifting stage – compared to their younger counterparts. Thus this task may be used to identify mechanisms underlying individual differences in decline of frontal-mediated performances with age.
PMCID: PMC2877277  PMID: 20498348
Aging; Mice; Set-Shifting; Cognition; Odor; Attention; Executive Function; Memory
20.  The effects of globin on microarray-based gene expression analysis of mouse blood 
Mammalian Genome  2010;21(5-6):268-275.
The use of mouse blood as a model for human blood is often considered in the development of clinically relevant, gene expression-based disease biomarkers. However, the ability to derive biologically meaningful insights from microarray-based gene expression patterns in mouse whole blood, as in human whole blood, is hindered by high levels of globin mRNA. In order to characterize the effects of globin reduction on gene expression of peripheral mouse blood, we performed gene set enrichment analysis on genes identified as expressed in blood via microarray-based genome-wide transcriptome analysis. Depletion of globin mRNA enhanced the quality of microarray data as shown by improved gene expression detection and increased sensitivity. Compared to genes expressed in whole blood, genes detected as expressed in blood following globin reduction were enriched for low abundance transcripts implicated in many biological pathways, including development, g-protein signaling, and immune response. Broadly, globin reduction resulted in improved detection of expressed genes that serve as molecular binding proteins and enzymes in cellular metabolism, intracellular transport/localization, transcription, and translation, as well as genes that potentially could act as biomarkers for diseases such as schizophrenia. These significantly enriched pathways overlap considerably with those identified in globin-reduced human blood suggesting that globin-reduced mouse blood gene expression studies may be useful for identifying genes relevant to human disease. Overall, the results of this investigation provide a better understanding of the impact of reducing globin transcripts in mouse blood and highlight the potential of microarray-based, globin-reduced, mouse blood gene expression studies in biomarker development.
Electronic supplementary material
The online version of this article (doi:10.1007/s00335-010-9261-y) contains supplementary material, which is available to authorized users.
PMCID: PMC2890980  PMID: 20473674
21.  Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain 
Age  2010;32(3):309-322.
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn’s post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (rs = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.
PMCID: PMC2926850  PMID: 20422297
Aging; Brain immunophilins; FKBP51; FKBP52; Glucocorticoid receptor signaling; Object recognition test
22.  5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity in mice 
Although it is well established that hallucinogens act as 5-HT2A and 5-HT2C receptor agonists, little is known about the relative contributions of 5-HT2A and 5-HT2C receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT2A and 5-HT2C receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose response function, with lower doses (0.625–5.0 mg/kg) increasing and higher doses (≥10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT2A receptor KO mice, suggesting the involvement of 5-HT2A receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT2A KO mice and attenuated by pretreatment with the selective 5-HT2C/2B antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT2C receptors, an interpretation that is supported by the finding that the selective 5-HT2C agonist WAY 161,503 produces reductions in locomotor activity that are potentiated in 5HT2A KO mice. These results demonstrate for the first time that 5-HT2A and 5-HT2C receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity.
PMCID: PMC2697271  PMID: 19322172
hallucinogen; mice; locomotor activity; knockout; serotonin; DOI
23.  Spontaneous Nicotine Withdrawal Potentiates the Effects of Stress in Rats 
Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-β-erythroidine hydrobromide (DHβE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.
PMCID: PMC2648847  PMID: 18033237
nicotine; withdrawal; anxiety; startle; rat
24.  Role of Dopamine D1 and D2 Receptors in CRF-Induced Disruption of Sensorimotor Gating 
Corticotropin-releasing factor (CRF), a neuropeptide released during stress, has been reported to modulate startle behavior, including reducing the threshold for acoustic startle responding and reducing prepulse inhibition (PPI). The central mechanisms mediating CRF system regulation of startle and PPI are still unclear. Some antipsychotic drugs attenuate CRF-induced deficits in PPI in rats and mice. Here we tested the hypothesis that indirect activation of DA1-receptors (D1) and DA2-receptors (D2) contributes to the effects of CRF on PPI. We compared the effect of central administration of h/r-CRF (0.2-0.6 nmol) on PPI in mice with either a D1 or D2 receptor null mutation (knockout, KO) or in mice pretreated with D1 or D2 receptor antagonists SCH23390 (1 mg/kg) or haloperidol (1 mg/kg). D1 and D2 KO mice exhibited no significant differences in their sensitivity to CRF-induced disruptions of PPI. Similarly, neither SCH23390 nor haloperidol pretreatment altered the CRF-induced disruption in PPI, although both increased PPI at baseline. CRF-induced increases in startle also remained unchanged by any of the DA receptor manipulations. These results indicate that neither D1- nor D2-receptor activation is necessary for CRF to exert its effects on acoustic startle and PPI in mice.
PMCID: PMC1892615  PMID: 17324452
CRH (corticotropin-releasing hormone); CRF; dopamine; haloperidol; SCH23390; prepulse inhibition; startle; knockout mice
25.  Role of Corticotropin Releasing Factor in Anxiety Disorders: A Translational Research Perspective 
Hormones and behavior  2006;50(4):550-561.
Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety.
PMCID: PMC1884405  PMID: 16870185
CRH; CRF; Posttraumatic stress disorder; Anxiety; Panic disorder; Startle

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