Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Evidence for altered brain reactivity to norepinephrine in Veterans with a history of traumatic stress.

BACKGROUND: Increases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). This increased signaling may result from increased norepinephrine (NE) release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. METHODS: Using a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF). CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS), which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS) and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]). Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. RESULTS: Fifty-two Veterans met criteria for a history of trauma exposure; of these, 36 met criteria for PTSD. CSF NE levels were not significantly different in Veterans with a history of trauma compared to those without, nor in Veterans with PTSD as compared to those without. Veterans with a history of trauma and who were not using the medication prazosin demonstrated a significantly more positive correlation between CSF NE and behavioral symptom expression than Veterans who had not experienced traumatic stress. No relationship between CSF NE and behavioral symptom expression was found in Veterans who had experienced traumatic stress and were taking prazosin at the time of the assessments. CONCLUSIONS: These results are consistent with increased central nervous system responsiveness to noradrenergic signaling in individuals with a history of traumatic exposure, raising the possibility that there may be long-lasting physiologic effects of trauma-exposure that exist independently of whether an individual meets criteria for PTSD at any given point in time. Exploration of the mechanism by which brain responsiveness to NE is modulated following trauma holds the possibility of finding new strategies for both preventing and treating PTSD.

Chronic Hypopituitarism Associated with Increased Postconcussive Symptoms Is Prevalent after Blast-Induced Mild Traumatic Brain Injury.

The most frequent injury sustained by US service members deployed to Iraq or Afghanistan is mild traumatic brain injuries (mTBI), or concussion, by far most often caused by blast waves from improvised explosive devices or other explosive ordnance. TBI from all causes gives rise to chronic neuroendocrine disorders with an estimated prevalence of 25-50%. The current study expands upon our earlier finding that chronic pituitary gland dysfunction occurs with a similarly high frequency after blast-related concussions. We measured circulating hormone levels and accessed demographic and testing data from two groups of male veterans with hazardous duty experience in Iraq or Afghanistan. Veterans in the mTBI group had experienced one or more blast-related concussion. Members of the deployment control (DC) group encountered similar deployment conditions but had no history of blast-related mTBI. 12 of 39 (31%) of the mTBI participants and 3 of 20 (15%) veterans in the DC group screened positive for one or more neuroendocrine disorders. Positive screens for growth hormone deficiency occurred most often. Analysis of responses on self-report questionnaires revealed main effects of both mTBI and hypopituitarism on postconcussive and posttraumatic stress disorder (PTSD) symptoms. Symptoms associated with pituitary dysfunction overlap considerably with those of PTSD. They include cognitive deficiencies, mood and anxiety disorders, sleep problems, diminished quality of life, deleterious changes in metabolism and body composition, and increased cardiovascular mortality. When such symptoms are due to hypopituitarism, they may be alleviated by hormone replacement. These findings suggest consideration of routine post-deployment neuroendocrine screening of service members and veterans who have experienced blast-related mTBI and are reporting postconcussive symptoms.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia.

OBJECTIVE: This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD. METHODS: Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n = 305), participants with aMCI (n = 22), and AD dementia (n = 94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index. RESULTS: Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients ± standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0 ± 0.2, P = 1.0; MCI, 1.4 ± 0.7, P = .14; and AD 1.1 ± 0.4, P = .032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2 ± 0.3, P = .007). CONCLUSIONS: Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress.

DOPA Decarboxylase Modulates Tau Toxicity.

BACKGROUND: The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. METHODS: To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. RESULTS: We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. CONCLUSIONS: Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.

Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats.

In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression.

Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine.

Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer's disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 µg/µl), animals administered the 5 µg/µl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 µg/µl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 µg/µl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 µg/µl dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 µg/µl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or l-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 µg/µl) demonstrated compensatory changes of increased firing frequency, a more irregular firing pattern, and a higher percentage of cells firing in bursts. These results indicate that depressive-like behavior in mice is observed following the administration of 6-OHDA and the loss of LC noradrenergic neurons; however, the depressive-like behavior correlates positively with the number of surviving LC neurons with 6-OHDA administration. This data suggests the depression observed in MCI subjects and in the early stages of AD may due to the hypothesized early, minimal loss of LC neurons with remaining LC neurons being more active than normal.

Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span.

Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21-100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.

Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration.

Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and dopaminergic system in PD.

An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression.

BACKGROUND: Recent interest has demonstrated the nucleus accumbens (NAcc) as a potential target for the treatment of depression with deep brain stimulation (DBS). OBJECTIVE: To demonstrate that DBS of the NAcc is an effective treatment modality for depression and that chemical and structural changes associated with these behavioral changes are markers of neuroplasticity. METHODS: A deep brain stimulator was placed in the NAcc of male Wistar-Kyoto rats. Groups were divided into sham (no stimulation), intermittent (3 h/d for 2 weeks), or continuous (constant stimulation for 2 weeks). Exploratory and anxietylike behaviors were evaluated with the open-field test before and after stimulation. Tissue samples of the prefrontal cortex (PFC) were processed with Western blot analysis of markers of noradrenergic activity that included the noradrenergic synthesizing enzyme tyrosine hydroxylase. Analysis of tissue levels for catecholamines was achieved with high-performance liquid chromatography. Morphological properties of cortical pyramidal neurons were assessed with Golgi-Cox staining. RESULTS: Subjects undergoing intermittent and continuous stimulation of the NAcc exhibited an increase in exploratory behavior and reduced anxietylike behaviors. Tyrosine hydroxylase expression levels were decreased in the PFC after intermittent and continuous DBS, and dopamine and norepinephrine levels were decreased after continuous stimulation. Golgi-Cox staining indicated that DBS increased the length of apical and basilar dendrites in pyramidal neurons of the PFC. CONCLUSION: Deep brain stimulation induces behavioral improvement in and neurochemical and morphological alterations of the PFC that demonstrate changes within the circuitry of the brain different from the target area of stimulation. This observed dendritic plasticity may underlie the therapeutic efficacy of this treatment.