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1.  The human parental brain: In vivo neuroimaging 
Interacting parenting thoughts and behaviors, supported by key brain circuits, critically shape human infants’ current and future behavior. Indeed, the parent–infant relationship provides infants with their first social environment, forming templates for what they can expect from others, how to interact with them and ultimately how they go on to themselves to be parents. This review concentrates on magnetic resonance imaging experiments of the human parent brain, which link brain physiology with parental thoughts and behaviors. After reviewing brain imaging techniques, certain social cognitive and affective concepts are reviewed, including empathy and trust—likely critical to parenting. Following that is a thorough study-by-study review of the state-of-the-art with respect to human neuroimaging studies of the parental brain—from parent brain responses to salient infant stimuli, including emotionally charged baby cries and brief visual stimuli to the latest structural brain studies. Taken together, this research suggests that networks of highly conserved hypothalamic–midbrain–limbic–paralimbic–cortical circuits act in concert to support parental brain responses to infants, including circuits for limbic emotion response and regulation. Thus, a model is presented in which infant stimuli activate sensory analysis brain regions, affect corticolimbic limbic circuits that regulate emotional response, motivation and reward related to their infant, ultimately organizing parenting impulses, thoughts and emotions into coordinated behaviors as a map for future studies. Finally, future directions towards integrated understanding of the brain basis of human parenting are outlined with profound implications for understanding and contributing to long term parent and infant mental health.
doi:10.1016/j.pnpbp.2010.10.017
PMCID: PMC4329016  PMID: 21036196
Attachment; Brain imaging; fMRI; Parent–child relationships; Parenting and caregiving
2.  Betaxolol, a selective β1-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats 
Background
Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on β-adrenergic receptor (β1 and β2) expression in the amygdala.
Methods
Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that β1–adrenergic receptor, but not β2–adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective β1–adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 hours following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 hours following the last betaxolol injection. Following behavioral testing, betaxolol effects on β1-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal.
Results
Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with betaxolol during early cocaine withdrawal significantly decreased β1-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals.
Conclusions
The present findings suggest that the anxiolytic-like effect of betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar β1-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.
doi:10.1016/j.pnpbp.2007.04.005
PMCID: PMC4287233  PMID: 17513029
norepinephrine; cocaine; amygdala; anxiety; withdrawal; beta-adrenergic receptor antagonists; betaxolol; western blot; elevated plus maze; rat
3.  Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood 
This preclinical study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Antipsychotic effect was indexed by a drug’s suppressive effect on avoidance responding in a rat conditioned avoidance response (CAR) model. Male adolescent Sprague-Dawley rats were first treated with risperidone (1.0 mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days from postnatal days P 40 to 44. After they became adults (~P 80–84), they were switched to olanzapine (0.5 mg/kg, sc), clozapine (5.0 mg/kg, sc) or vehicle treatment and tested for avoidance for additional 5 days. During the adolescent period, repeated risperidone treatment produced a persistent inhibition of avoidance response. Throughout the 5 days of adulthood drug testing, rats previously treated with risperidone in adolescence made significantly fewer avoidance responses than the vehicle ones when they all were switched to olanzapine, indicating a risperidone-induced enhancement of behavioral sensitivity to olanzapine. In contrast, when switched to clozapine, rats previously treated with risperidone made significantly more avoidance responses than the vehicle rats, indicating a risperidone-induced decrease of behavioral sensitivity to clozapine. Performance in the prepulse inhibition of acoustic startle response in adulthood was not altered by adolescent risperidone treatment. Collectively, adolescent risperidone exposure induced a long-term change in behavioral sensitivity to other atypical antipsychotic drugs, with the specific direction of change (i.e. increase or decrease) dependent on the drug. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and may also have significant clinical implications for antipsychotic treatment of chronic patients with an early onset of psychotic symptoms.
doi:10.1016/j.pnpbp.2013.10.005
PMCID: PMC3859461  PMID: 24140929
Risperidone; Olanzapine; Clozapine; Conditioned avoidance response; Adolescence; Sensitization
4.  Correspondence of Executive Function Related Functional and Anatomical Alterations in Aging Brain 
Neurocognitive aging studies have focused on age-related changes in neural activity or neural structure but few studies have focused on relationships between the two. The present study quantitatively reviewed 24 studies of age-related changes in fMRI activation across a broad spectrum of executive function tasks using activation likelihood estimation (ALE) and 22 separate studies of age-related changes in gray matter using voxel-based morphometry (VBM). Conjunction analyses between functional and structural alteration maps were constructed. Overlaps were only observed in the conjunction of dorsalateral prefrontal cortex (DLPFC) gray matter reduction and functional hyperactivation but not hypoactivation. It was not evident that the conjunctions between gray matter and activation were related to task performance. Theoretical implications of these results are discussed.
doi:10.1016/j.pnpbp.2013.09.001
PMCID: PMC3870052  PMID: 24036319
aging; dorsolateral prefrontal cortex; efficiency; executive function; meta-analysis; plasticity
5.  Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats 
Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We investigated the effects of 14-day nicotine exposure (6.32 mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to be increased during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use.
doi:10.1016/j.pnpbp.2013.09.007
PMCID: PMC3858513  PMID: 24060391
Delayed reward; delay discounting; high and low impulsive rats; Wistar rats
6.  The utility of zebrafish to study the mechanisms by which ethanol affects social behavior and anxiety during early brain development 
Exposure to moderate levels of ethanol during brain development has a number of effects on social behavior but the molecular mechanisms that mediate this are not well understood. Gaining a better understanding of these factors may help to develop therapeutic interventions in the future. Zebrafish offer a potentially useful model in this regard. Here, we introduce a zebrafish model of moderate prenatal ethanol exposure. Embryos were exposed to 20 mM ethanol for seven days (48hpfs–9dpf) and tested as adults for individual social behavior and shoaling. We also tested their basal anxiety with the novel tank diving test. We found that the ethanol-exposed fish displayed reductions in social approach and shoaling, and an increase in anxiety in the novel tank test. These behavioral differences corresponded to differences in hrt1aa, slc6a4 and oxtr expression. Namely, acute ethanol caused a spike in oxtr and ht1aa mRNA expression, which was followed by down-regulation at 7dpf, and an up-regulation in slc6a4 at 72hpf. This study confirms the utility of zebrafish as a model system for studying the molecular basis of developmental ethanol exposure. Furthermore, it proposes a putative developmental mechanism characterized by ethanol-induced OT inhibition leading to suppression of 5-HT and up-regulation of 5-HT1A, which leads, in turn, to possible homeostatic up-regulation of 5-HTT at 72hpf and subsequent imbalance of the 5-HT system.
doi:10.1016/j.pnpbp.2014.03.011
PMCID: PMC4186787  PMID: 24690524
Moderate prenatal ethanol; Oxytocin; Serotonin; Social; Vasopressin; Zebrafish
7.  Can Bariatric Surgery Reduce Risk of Alzheimer’s Disease? 
Recent studies demonstrate that obesity is independently associated with poor neurocognitive outcomes, including cognitive impairment, increased risk for dementia, and regional alterations in brain structure. Bariatric surgery is an effective treatment for obesity and initial findings suggest that it may result in cognitive improvements. The current paper reviews and integrates recent research in this area, with a focus on potential mediators and moderators of neuropsychological outcome in bariatric surgery patients, including anesthetic and nutritional complications and proposes novel avenues for continued study in this area.
doi:10.1016/j.pnpbp.2012.06.021
PMCID: PMC3491171  PMID: 22771689
obesity; Alzheimer’s disease; bariatric surgery; cognitive function
8.  Anesthesia, Surgery, Illness and Alzheimer’s Disease 
Patients and their families have, for many decades, detected subtle changes in cognition subsequent to surgery, and only recently has this been subjected to scientific scrutiny. Through a combination of retrospective human studies, small prospective biomarker studies, and experiments in animals, it is now clear that durable consequences of both anesthesia and surgery occur, and that these intersect with the normal processes of aging, and the abnormal processes of chronic neurodegeneration. It is highly likely that inflammatory cascades are at the heart of this intersection, and if confirmed, this suggests a therapeutic strategy to mitigate enhanced neuropathology in vulnerable surgical patients.
doi:10.1016/j.pnpbp.2012.06.011
PMCID: PMC3509241  PMID: 22729032
neuroinflammation; peripheral inflammation; cytokines; Alzheimer transgenic mice; POCD; biomarkers
9.  General anesthetics and β-amyloid protein 
With roughly 234 million people undergoing surgery with anesthesia each year worldwide, it is important to determine whether commonly used anesthetics can induce any neurotoxicity. Alzheimer's disease (AD) is the most common form of age-related dementia, and a rapidly growing health problem. Several studies suggest that anesthesia could be associated with the development of AD. Moreover, studies in cultured cells and animals show that commonly used inhalation anesthetics may induce changes consistent with AD neuropathogenesis, e.g., β-amyloid protein accumulation. Therefore, in this mini review, we focus on the recent research investigating the effects of commonly used anesthetics including isoflurane, sevoflurane, desflurane, nitrous oxide, and propofol, on Aβ accumulation in vitro and in vivo. We further discuss the future direction of the research determining the effects of anesthetics on β-amyloid protein accumulation.
doi:10.1016/j.pnpbp.2012.08.002
PMCID: PMC3510311  PMID: 22918033
10.  Anesthetic effects in Alzheimer transgenic mouse models 
Research has improved the diagnosis of Alzheimer’s disease, and at earlier stages, but effective therapy continues to be elusive. Current effort is focused on delay. Environmental factors are thought to interact with genetics to modulate the progression of the disease, and one such environmental factor is exposure to general anesthetics. The possibility that some anesthetic effects have long-term consequences is of general interest and concern. The difficulty of studying a chronic, age-related disease in humans combined with the fact that anesthetics are rarely given without surgery, has led to a focus on animal models. Transgenic mouse models have been developed to mimic the hallmarks of Alzheimer’s disease, including amyloid beta accumulation (plaque), neurofibrillary tangles, and cognitive dysfunction. While none of the models recapitulate the human disease with high fidelity, they allow a first look at anesthetic - Alzheimer interactions in a reasonable time frame. In studies found to date, none have concluded that anesthetics alone cause a significant change in cognitive decline, but rather an acceleration in Alzheimer neuropathology. Further studies are required to define the best anesthetic paradigm for our elderly population to mitigate changes in neuropathology and potentially cognition.
doi:10.1016/j.pnpbp.2012.06.007
PMCID: PMC3521854  PMID: 22705294
isoflurane; sevoflurane; desflurane; amyloidopathy; tauopathy; anesthetic sensitivity
11.  Anesthesia and Tau Pathology 
Alzheimer’s disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration.
doi:10.1016/j.pnpbp.2013.03.004
PMCID: PMC3741335  PMID: 23535147
Anesthesia; Alzheimer’s disease; Tau; Kinase; Phosphatase
12.  Dual effects of neuroprotection and neurotoxicity by general anesthetics: Role of intracellular calcium homeostasis 
Although general anesthetics have long been considered neuroprotective, there are growing concerns about neurotoxicity. Preclinical studies clearly demonstrated that commonly used general anesthetics are both neuroprotective and neurotoxic, with unclear mechanisms. Recent studies suggest that differential activation of inositol 1,4,5-trisphosphate receptors, a calcium release channel located on the membrane of endoplasmic reticulum (ER), play important role on determining the fate of neuroprotection or neurotoxicity by general anesthetics. General anesthetics at low concentrations for short duration are sublethal stress factors which induce endogenous neuroprotective mechanisms and provide neuroprotection via adequate activation of InsP3R and moderate calcium release from ER. On the other hand, general anesthetics at high concentrations for prolonged duration are lethal stress factors which induce neuronal damage by over activation of InsP3R and excessive and abnormal Ca2+ release from ER. This review emphasizes the duel effects of both neuroprotection and neurotoxicity via differential regulation of intracellular Ca2+ homeostasis by commonly used general anesthetics and recommends strategy to maximize neuroprotective but minimize neurotoxic effects of general anesthetics.
doi:10.1016/j.pnpbp.2013.05.009
PMCID: PMC3791176  PMID: 23721657
13.  Influence of Aripiprazole Pretreatment on the Reinforcing Effects of Methamphetamine In Humans 
Methamphetamine use disorders remain a significant public health concern. Methamphetamine produces its behavioral effects by facilitating release of monoamines like dopamine (DA) and serotonin (5-HT). Results from animal studies show that acute pretreatment with DA and 5-HT antagonists attenuates the effects of methamphetamine, but this area remains largely unexplored in humans. This study sought to assess whether aripiprazole, a partial agonist at D2/5-HT1A receptors and an antagonist at 5-HT2A receptors, would attenuate the reinforcing and subject-rated effects of oral methamphetamine. Seven subjects with histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 4, 8 or 16 mg) following acute pretreatment with aripiprazole (0 and 15 mg). During each Sampling Session, subjects also completed a battery of subject-rated, cardiovascular, and other performance measures. In subsequent Self-Administration Sessions, subjects were provided the opportunity to earn the previously sampled methamphetamine dose on a progressive-ratio procedure. Methamphetamine functioned as a reinforcer, produced prototypical stimulant-like subject-rated and cardiovascular effects (e.g., increased ratings of Stimulated; elevated blood pressure). Aripiprazole reduced methamphetamine self-administration and attenuated some of the positive subject-rated effects of methamphetamine (e.g., ratings of Like Drug). These results indicate that acute aripiprazole pretreatment attenuates the abuse-related effects of methamphetamine.
doi:10.1016/j.pnpbp.2013.08.007
PMCID: PMC3825805  PMID: 23994622
Methamphetamine; Aripiprazole; Monoamines; Humans
14.  Antioxidants as potential therapeutics for neuropsychiatric disorders 
Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and nongenetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders.
doi:10.1016/j.pnpbp.2012.10.017
PMCID: PMC3615047  PMID: 23123357
15.  Potential translational targets revealed by linking mouse grooming behavioral phenotypes to gene expression using public databases 
Rodent self-grooming is an important, evolutionarily conserved behavior, highly sensitive to pharmacological and genetic manipulations. Mice with aberrant grooming phenotypes are currently used to model various human disorders. Therefore, it is critical to understand the biology of grooming behavior, and to assess its translational validity to humans. The present in-silico study used publicly available gene expression and behavioral data obtained from several inbred mouse strains in the open-field, light-dark box, elevated plus- and elevated zero-maze tests. As grooming duration differed between strains, our analysis revealed several candidate genes with significant correlations between gene expression in the brain and grooming duration. The Allen Brain Atlas, STRING, GoMiner and Mouse Genome Informatics databases were used to functionally map and analyze these candidate mouse genes against their human orthologs, assessing the strain ranking of their expression and the regional distribution of expression in the mouse brain. This allowed us to identify an interconnected network of candidate genes (which have expression levels that correlate with grooming behavior), display altered patterns of expression in key brain areas related to grooming, and underlie important functions in the brain. Collectively, our results demonstrate the utility of large-scale, high-throughput data-mining and in-silico modeling for linking genomic and behavioral data, as well as their potential to identify novel neural targets for complex neurobehavioral phenotypes, including grooming.
doi:10.1016/j.pnpbp.2012.10.015
PMCID: PMC4141078  PMID: 23123364
Grooming behavior; Anxiety in Mice; Neurophenotypes; Behavioral domains; Gene expression and omics
16.  Neural Predictors and Mechanisms of Cognitive Behavioral Therapy on Threat Processing in Social Anxiety Disorder 
Cognitive behavioral therapy (CBT) is “gold standard” psychotherapy for social anxiety disorder (SAD). Cognitive models posit that preferential processing of threat mediates excessive forms of anxiety, which is supported by exaggerated amygdala, insula, and cortical reactivity to threatening socio-emotional signals in SAD. However, little is known about neural predictors of CBT success or the mechanisms by which CBT exerts its therapeutic effects. Functional magnetic resonance imaging (fMRI) was conducted during responses to social signals of threat (fearful/angry faces) against positive signals (happy faces) in 14 patients with SAD before and after 12 weeks of CBT. For comparison, 14 healthy control (HC) participants also underwent two fMRI scans, 12 weeks apart. Whole-brain voxel-wise analyses showed therapeutic success was predicted by enhanced pre-treatment activation to threatening faces in higher-order visual (superior and middle temporal gyrus), cognitive, and emotion processing areas (dorsal anterior cingulate cortex, dorsomedial prefrontal cortex). Moreover, a group by time interaction was revealed in prefrontal regions (dorsomedial, medial gyrus) and insula. The interaction was driven by relatively greater activity during threat processing in SAD, which significantly reduced after CBT but did not significantly predict response to CBT. Therefore, pre-treatment cortical hyperactivity to social threat signals may serve as a prognostic indicator of CBT success in SAD. Collectively, CBT-related brain changes involved a reduction in activity in insula, prefrontal, and extrastriate regions. Results are consistent with cognitive models, which associate decreases in threat processing bias with recovery.
doi:10.1016/j.pnpbp.2013.05.004
PMCID: PMC3951971  PMID: 23665375
generalized social anxiety; fMRI; treatment; emotional faces; brain imaging
17.  Technical advances in the characterization of the complexity of sleep and sleep disorders 
The current clinical standard for quantifying sleep physiology is the laboratory polysomnogram, from which basic sleep-wake stages are determined. However, the complexity of sleep physiology has inspired alternative metrics that are providing additional insights into the rich dynamics of sleep. Electro-encephalography, magneto-encephalography, and functional magnetic resonance imaging represent advanced imaging modalities for understanding brain dynamics. These methods are complemented by autonomic measurements that provide additional important insights. We review here the spectrum of approaches that have been leveraged towards improved understanding of the complexity of sleep.
doi:10.1016/j.pnpbp.2012.09.017
PMCID: PMC3631575  PMID: 23174482
18.  A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats 
Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC–MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence.
doi:10.1016/j.pnpbp.2013.05.012
PMCID: PMC3773503  PMID: 23739535
Antinociception; Conditioned place preference; Heroin metabolites; Immunotherapy; Opioid dependence
19.  Physiologic Complexity and Aging: Implications for Physical Function and Rehabilitation 
The dynamics of most healthy physiological processes are complex, in that they are comprised of fluctuations with information-rich structure correlated over multiple temporospatial scales. Lipsitz and Goldberger (1992) first proposed that the aging process may be characterized by a progressive loss of physiologic complexity. We contend that this loss of complexity results in functional decline of the organism by diminishing the range of available, adaptive responses to the innumerable stressors of everyday life. From this relationship, it follows that rehabilitative interventions may be optimized by targeting the complex dynamics of human physiology, and by quantifying their effects using tools derived from complex systems theory. Here, we first discuss several caveats that one must consider when examining the functional and rehabilitative implications of physiologic complexity. We then review available evidence regarding the relationship between physiologic complexity and system functionality, as well as the potential for interventions to restore the complex dynamics that characterize healthy physiological function.
doi:10.1016/j.pnpbp.2012.08.020
PMCID: PMC3568237  PMID: 22985940
Complexity; Postural Control; Cardiovascular; Multiscale Entropy; Nonlinear
20.  Gene expression analysis of novel genes in the prefrontal cortex of major depressive disorder subjects 
Dysregulation of the glutamatergic system has been implicated not only in the treatment of major depressive disorder (MDD), but also in the excitotoxic effects of stress and anxiety on the prefrontal cortex, which may precede the onset of a depressive episode. Our previous studies demonstrate marked deficits in prominent postsynaptic proteins involved in glutamate neurotransmission in the prefrontal cortex (PFC), Brodmann’s area 10 (BA 10) from subjects diagnosed with major depressive disorder (MDD). In the same group of subjects we have identified deficits in expression and phosphorylation level of key components of the mammalian target of rapamycin (mTOR) signalling pathway, known to regulate translation initiation. Based on our previous findings, we have postulated that glutamate-dependent dysregulation of mTOR- initiated protein synthesis in the PFC may underlie the pathology of MDD. The aim of this study was to use the NanoString nCounter System to perform analysis of genes coding for glutamate transporters, glutamate metabolizing enzymes, neurotrophic factors and other intracellular signaling markers involved in glutamate signaling that were not previously investigated by our group in the PFC BA10 from subjects with MDD. We have analyzed a total of 200 genes from 16 subjects with MDD and 16 healthy controls. These are part of the same cohort used in our previous studies. Setting our cutoff p-value ≤ 0.01, marked upregulation of genes coding for mitochondrial glutamate carrier (GC1; p=0.0015), neuropilin 1 (NRP-1; p=0.0019), glutamate receptor ionotropic N-methyl-D-aspartate-associated protein 1 (GRINA; p=0.0060), and fibroblast growth factor receptor 1 (FGFR-1; p=0.010) was identified. No significant differences in expression of the remaining 196 genes were observed between MDD subjects and controls. While upregulation of FGFR-1 has been previously shown in MDD; abnormalities in GC-1, GRINA, and NRP-1 have not been reported. Therefore, this postmortem study identifies GC1, GRINA, and NRP-1 as novel factors associated with MDD; however, future studies will be needed to address the significance of these genes in the pathophysiology of depression and antidepressant activity.
doi:10.1016/j.pnpbp.2012.12.010
PMCID: PMC4089971  PMID: 23261523
prefrontal cortex; major depressive disorder; postmortem; gene expression; digital PCR
21.  Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats☆ 
Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.
doi:10.1016/j.pnpbp.2014.01.011
PMCID: PMC4011798  PMID: 24472317 CAMSID: cams4372
Brain slice electrophysiology; Cocaine; Dopamine; NMDA; Self-administration
22.  Response prediction to antidepressants using scalp and source-localized loudness dependence of auditory evoked potential (LDAEP) slopes 
The loudness-dependence of the auditory evoked potential (LDAEP) slope may be inversely related to serotonin (5-HT) neurotransmission. Thus, steep LDAEPs tend to predict a positive response to selective serotonin reuptake inhibitor (SSRI) antidepressants, which augment 5-HT. However, LDAEPs also predict outcome to antidepressants indirectly altering 5-HT (e.g. bupropion). Hence, the LDAEP’s predicative specificity and sensitivity to antidepressant response/outcome remains elusive. Scalp N1, P2 and N1/P2 LDAEP slopes and standardized low resolution brain electromagnetic tomography (sLORETA)-localized N1 and P2 LDAEP slopes were assessed in depressed individuals (N=51) at baseline, 1 and 12 weeks post-treatment with one of three antidepressant regimens [escitalopram (ESC) + bupropion (BUP), ESC or BUP]. Clinical response was greatest with ESC+BUP at week 1. Treatment responders had steep N1 sLORETA-LDAEP baseline slopes while non-responders had shallow ones. P2 sLORETA-LDAEP slope increases at 1 week existed in responders; decreases were noted in non-responders. Exploratory analyses indicated that more BUP and ESC responders versus non-responders had steep baseline N1 sLORETA-LDAEP slopes. Additionally, slight decreases in scalp P2 LDAEP by week 1 existed for ESC treatment, while slope increases existed with ESC+BUP treatment. Only baseline N1 sLORETA-LDAEP discriminated treatment responders/non-responders. This work confirms that certain LDAEP measures are associated with treatment outcome and appear to be differentially modulated with varying antidepressant drug regimens, though this should be confirmed using larger samples.
doi:10.1016/j.pnpbp.2013.01.012
PMCID: PMC3654010  PMID: 23360662
antidepressants; classification; serotonin; major depressive disorder (MDD); loudness-dependence of auditory evoked potentials (LDAEP)
23.  The Effect of Short-term Stress on Serotonin Gene Expression in High and Low Resilient Macaques 
Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. When stressed with a paradigm of relocation and diet for 60 days, or 2 menstrual cycles, highly stress resilient monkeys continue to ovulate during both stress cycles (HSR); medium stress resilient monkeys ovulate once (MSR) and stress sensitive monkeys do not ovulate for the entire 60 days (SS). This study examines serotonin-related gene expression in monkeys with different sensitivity to stress and exposed to 5 days of moderate stress. Monkeys were first characterized as HSR, MSR or SS. After resumption of menstrual cycles, each monkey was re-stressed for 5 days in the early follicular phase. The expression of 3 genes pivotal to serotonin neural function was assessed in the 3 groups of monkeys (n=4-5/group). Tryptophan hydroxylase 2 (TPH2), the serotonin reuptake transporter (SERT), and the 5HT1A autoreceptor mRNAs expression were determined at 4 morphological levels of the dorsal raphe nucleus with in situ hybridization (ISH) using digoxygenin-incorporated riboprobes. In addition, cFos was examined with immunohistochemistry. Positive pixel area and/or cell number were measured. All data were analyzed with ANOVA (3 groups) and with a t-test (2 groups). After 5 days of stress, TPH2, SERT, 5HT1A and cFos were significantly lower in the SS group than the HSR group (p < 0.05, all). This pattern of expression was the same as the pattern observed in the absence of stress in previous studies. Therefore, the ratio of the HSR/SS expression of each serotonergic gene was calculated in the presence and absence of stress. There was little or no difference in the ratio of HSR/SS gene expression in the presence or absence of stress. Moreover, cFos expression indicates that overall, cell activation in the dorsal raphe nucleus and periaquaductal gray is lower in SS than HSR animals. These data suggest that the serotonin system may set the sensitivity or resilience of the individual, but serotonin-related gene expression may not rapidly respond to moderate stress in nonhuman primates.
doi:10.1016/j.pnpbp.2013.01.013
PMCID: PMC3654014  PMID: 23357537
Stress; stress resilient; ovulation; amenorrhea; serotonin; macaques; gene expression
24.  Symptom Dimensions are Associated with Age of Onset and Clinical Course of Obsessive-Compulsive Disorder 
Meta-analysis of the heterogeneous symptoms of obsessive-compulsive disorder (OCD) has found a four-factor structure of symptom dimensions consisting of cleaning, forbidden thoughts, symmetry, and hoarding. Research into age of onset of symptom dimensions has yielded inconsistent results, and it is unknown whether symptoms along these dimensions differ in their clinical course. We assessed age of onset and clinical course of different OCD symptom dimensions in a large cohort of adult patients. Nine-hundred fifty-five subjects were assessed using the Dimensional Yale-Brown Obsessive-Compulsive Scale. For age of onset analysis, we tested across three methods of classification: (1) primary (more severe) symptom dimension (2) clinically significant symptoms within a dimension or (3) any symptoms within a dimension. Age of onset was defined as the earliest age of onset reported for any individual item within a symptom dimension. For analysis of different types of clinical course, we used chi-square tests to assess for differences between primary symptom dimensions. OCD symptoms in the symmetry dimension had an earlier age of onset than other OCD symptom dimensions. These findings remained significant across all three methods of classification and controlling for gender and comorbid tics. No significant differences were found between the other dimensions. Subjects with primary OCD symptoms in the forbidden thoughts dimension were more likely to report a waxing-and-waning course, whereas symmetry symptoms were less likely to be associated with a waxing-and-waning course.
doi:10.1016/j.pnpbp.2013.02.003
PMCID: PMC3654083  PMID: 23410525
Obsessive-Compulsive Disorder; Symptom Dimensions; Age of Onset; Clinical Course
25.  Angiotensin II’s role in sodium lactate-induced panic-like responses in rats with repeated urocortin 1 injections into the basolateral amygdala 
Rats treated with three daily urocortin 1 (UCN) injections into the basolateral amygdala (BLA; i.e., UCN/BLA-primed rats) develop prolonged anxiety-associated behavior and vulnerability to panic-like physiological responses (i.e., tachycardia, hypertension and tachypnea) following intravenous infusions of 0.5 M sodium lactate (NaLac, an ordinarily mild interoceptive stressor). In these UCN-primed rats, the osmosensitive subfornical organ (SFO) may be a potential site that detects increases in plasma NaLac and mobilizes panic pathways since inhibiting the SFO blocks panic following NaLac in this model. Furthermore, since SFO neurons synthesize angiotensin II (A-II), we hypothesized that the SFO projects to the BLA and releases A-II to mobilizing panic responses in UCN/BLA-primed rats following NaLac infusions. To test this hypothesis, rats received daily bilateral injections of UCN or vehicle into the BLA daily for 3 days. Five to seven days following the intra-BLA injections, we microinjected either the nonspecific A-II type 1 (AT1r) and 2 (AT2r) receptor antagonist saralasin, or the AT2r-selective antagonist PD123319 into the BLA prior to the NaLac challenge. The UCN/BLA-primed rats pre-injected with saralasin, but not PD123319 or vehicle, had reduced NaLac-induced anxiety-associated behavior and panic-associated tachycardia and tachypnea responses. We then confirmed the presence of AT1rs in the BLA using immunohistochemistry which, combined with the previous data, suggest that A-II’s panicogenic effects in the BLA is AT1r dependent. Surprisingly, the SFO had almost no neurons that directly innervate the BLA, which suggests an indirect pathway for relaying the NaLac signal. Overall these results are the first to implicate A-II and AT1rs as putative neurotransmitter-receptors in NaLac induced panic-like responses in UCN/BLA-primed rats.
doi:10.1016/j.pnpbp.2013.02.014
PMCID: PMC3665353  PMID: 23523745
Anxiety; panic; angiotensin; circumventricular organ; amygdala; GABA; saralasin

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