The influence of deployment stress and life stress on Post-Traumatic Stress Disorder (PTSD) diagnosis among military personnel.

There is increasing recognition that traumatic stress encountered throughout life, including those prior to military service, can put individuals at increased risk for developing Posttraumatic Stress Disorder (PTSD). The purpose of this study was to examine the association of both traumatic stress encountered during deployment, and traumatic stress over one's lifetime on probable PTSD diagnosis. Probable PTSD diagnosis was compared between military personnel deployed in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF; N = 21,499) and those who have recently enlisted (N = 55,814), using data obtained from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Probable PTSD diagnosis was assessed using the PTSD Checklist. The effect of exposure to multiple types (i.e. diversity) of traumatic stress and the total quantity (i.e. cumulative) of traumatic stress on probable PTSD diagnosis was also compared. Military personnel who had been deployed experienced higher rates of PTSD symptoms than new soldiers. Diversity of lifetime traumatic stress predicted probable PTSD diagnosis in both groups, whereas cumulative lifetime traumatic stress only predicted probable PTSD for those who had been deployed. For deployed soldiers, having been exposed to various types of traumatic stress during deployment predicted probable PTSD diagnosis, but cumulative deployment-related traumatic stress did not. Similarly, the total quantity of traumatic stress (i.e. cumulative lifetime traumatic stress) did not predict probable PTSD diagnosis among new soldiers. Together, traumatic stress over one's lifetime is a predictor of probable PTSD for veterans, as much as traumatic stress encountered during war. Clinicians treating military personnel with PTSD should be aware of the impact of traumatic stress beyond what occurs during war.

Control of arousal through neuropeptide afferents of the locus coeruleus.

The locus coeruleus-norepinephine (LC-NE) system is implicated in mediating several aspects of arousal. Alterations in LC neuronal discharge is associated with distinct changes in behavior, cognition, sensory processing and regulation of the sleep-wake cycle. Changes in LC output and subsequent release of NE in target brain regions help adjust arousal state to respond appropriately to environmental conditions and behavioral circumstances. One way in which LC activity is controlled is through release of endogenous neuropeptides. Based on the sleep-wake cycle and environmental cues specific neuropeptide afferent systems are activated, innervating the LC. These neuropeptides include: corticotropin releasing factor (CRF), orexin (ORX), endogenous opioids, substance P (SP), melanin-concentrating hormone (MCH), neuropeptide Y (NPY) and somatostatin (SS). This review summarizes studies examining the neuroanatomical projections of these neuropeptides, their receptors in the LC, the actions on LC neurons and downstream NE release, as well as the behavioral and cognitive effects associated individual neuropeptide-mediated innervation of the LC. Finally, the relationship between individual neuropeptides, the LC-NE system and various clinical disorders is discussed, providing evidence for possible therapeutic targets for treatment of several arousal- and stress-related disorders. This article is part of a Special Issue entitled SI: Noradrenergic System.

Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its Coherence with the Prefrontal Cortex.

Early life stress is associated with the development of psychiatric disorders. Because the locus coeruleus-norepinephrine (LC-NE) system is a major stress-response system that is implicated in psychopathology, developmental differences in the response of this system to stress may contribute to increased vulnerability. Here LC single unit and network activity were compared between adult and adolescent rats during resident-intruder stress. In some rats, LC and medial prefrontal cortex (mPFC) coherence was quantified. The initial stress tonically activated LC neurons and induced theta oscillations, while simultaneously decreasing LC auditory-evoked responses in both age groups. Stress increased LC-mPFC coherence within the theta range. With repeated exposures, adolescent LC neuronal and network activity remained elevated even in the absence of the stressor and were unresponsive to stressor presentation. In contrast, LC neurons of adult rats exposed to repeated social stress were relatively inhibited in the absence of the stressor and mounted robust responses upon stressor presentation. LC sensory-evoked responses were selectively blunted in adolescent rats exposed to repeated social stress. Finally, repeated stress decreased LC-mPFC coherence in the high frequency range (beta and gamma) while maintaining strong coherence in the theta range, selectively in adolescents. Together, these results suggest that adaptive mechanisms that promote stress recovery and maintain basal activity of the brain norepinephrine system in the absence of stress are not fully developed or are vulnerable stress-induced impairments in adolescence. The resulting sustained activation of the LC-NE system after repeated social stress may adversely impact cognition and future social behavior of adolescents.

Effects of intracerebroventricular corticotropin releasing factor on sensory-evoked responses in the rat visual thalamus.

Corticotropin releasing factor (CRF) coordinates the brain׳s responses to stress. Recent evidence suggests that CRF-mediated activation of the locus coeruleus-norepinephrine (LC-NE) system contributes to alterations in sensory signal processing during stress. However, it remains unclear whether these actions are dependent upon the degree of CRF release. Using intracerebroventricular (ICV) infusions, we examine the dose-dependent actions of CRF on sensory-evoked discharges of neurons in the dorsal lateral geniculate nucleus of the thalamus (dLGN). The LGN is the primary relay for visual signals from retina to cortex, receiving noradrenergic modulation from the LC. In vivo extracellular recording in anesthetized rats was used to monitor single dLGN neuron responses to light flashes at three different stimulus intensities before and after administration of CRF (0.1, 0.3, 1.0, 3.0 or 10.0 µg). CRF produced three main effects on dLGN stimulus evoked activity: (1) increased magnitude of sensory evoked discharges at moderate doses, (2) decreased response latency, and (3) dose-dependent increases in the number of cells responding to a previously sub-threshold (low intensity) stimulus. These modulatory actions were blocked or attenuated by intra-LC infusion of a CRF antagonist prior to ICV CRF administration. Moreover, intra-LC administration of CRF (10 ng) mimicked the facilitating effects of moderate doses of ICV CRF on dLGN neuron responsiveness to light stimuli. These findings suggest that stressor-induced changes in sensory signal processing cannot be defined in terms of a singular modulatory effect, but rather are multi-dimensional and dictated by variable degrees of activation of the CRF-LC-NE system.

The impact of hemodynamic stress on sensory signal processing in the rodent lateral geniculate nucleus.

Hemodynamic stress via hypotensive challenge has been shown previously to cause a corticotropin-releasing factor (CRF)-mediated increase in tonic locus coeruleus (LC) activity and consequent release of norepinephrine (NE) in noradrenergic terminal fields. Although alterations in LC-NE can modulate the responsiveness of signal processing neurons along sensory pathways, little is understood regarding how continuous CRF-mediated activation of LC-NE output due to physiologically relevant stressor affects downstream target cell physiology. The goal of the present study was to investigate the effects of a physiological stressor [hemodynamic stress via sodium nitroprusside (SNP) i.v.] on stimulus evoked responses of sensory processing neurons that receive LC inputs. In rat, the dorsal lateral geniculate nucleus (dLGN) of the thalamus is the primary relay for visual information and is a major target of the LC-NE system. We used extracellular recording techniques in the anesthetized rat monitor single dLGN neuron activity during repeated presentation of light stimuli before and during hemodynamic stress. A significant decrease in magnitude occurred, as well as an increase in latency of dLGN stimulus-evoked responses were observed during hemodynamic stress. In another group of animals the CRF antagonist DpheCRF12-41 was infused onto the ipsilateral LC prior to SNP administration. This infusion blocked the hypotension-induced changes in dLGN stimulus-evoked discharge. These results show that CRF-mediated increases in LC-NE due to hemodynamic stress disrupts the transmission of information along thalamic-sensory pathways by: (1) initially reducing signal transmission during onset of the stressor and (2) decreasing the speed of stimulus evoked sensory transmission.

Methylphenidate and atomoxetine enhance sensory-evoked neuronal activity in the visual thalamus of male rats.

Attention deficits and inappropriate regulation of sensory signal processing are hallmarks of many neuropsychiatric conditions, including attention deficit hyperactivity, for which methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed therapeutic treatments. Despite their widespread use and known mechanism of blocking reuptake of catecholamine transmitters in the brain, the resultant actions on individual neuron and neural circuit function that lead to therapeutic efficacy are poorly understood. Given the ability of MPH and ATX to improve cognitive performance in humans and rodent assays of attention, we were interested in their influence on early sensory processing in the dorsal lateral geniculate nucleus (dLGN), the primary thalamic relay for visual information from the retina to the visual cortex. In male rats, dLGN neuronal responses to light stimuli were altered in multiple ways after doses of MPH or ATX observed to enhance performance in visually guided assays of attention (MPH = 2 mg/kg; ATX = 0.5 mg/kg). Latencies to response onset and to the peak of the primary response were decreased, while the peak intensity and area of the primary response were increased. In addition, some cells that were unresponsive to light stimuli prior to drug treatment displayed a "gating effect," wherein prominent responses to light stimuli were evident after drug administration. Our results begin to reveal unique effects of MPH and ATX in enhancing sensory signal transmission through visual circuitry, and may yield new insights for understanding the pathophysiology of certain cognitive disorders and inform development of improved therapeutic treatments for these conditions.