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The neuropeptide galanin is a potential therapeutic target for treating stress-related disorders, such as post-traumatic stress disorder (PTSD); however, its effects on contextual fear conditioning (CFC), an accepted animal model of PTSD, are not well understood. Dysregulation of the medial prefrontal cortex (mPFC) is implicated in PTSD. We investigated the effects of galanin (1 ug) administrated bilaterally into the prelimbic cortex, a division of the mPFC, on the consolidation, expression, and extinction of CFC of male Sprague-Dawley rats. Galanin administration significantly reduced consolidation and expression of CFC, but had no effect on retention or retrieval of extinction learning. These data further implicate galanin as a potential therapeutic target for treating stress-related disorders, particularly those characterized by aberrant emotional memory., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer׳s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Rats selectively bred for high- and low-capacity for running on a treadmill (HCR; LCR) also differ in wheel-running behavior, but whether wheel-running can be explained by intrinsic or adaptive brain mechanisms is not as yet understood. It is established that motivation of locomotory behavior is driven by dopaminergic transmission in mesolimbic and mesostriatal systems. However, whether voluntary wheel running is associated with enkephalinergic activity in the ventral striatum is not known., Materials and Methods: 40 male (20 HCR and 20 LCR) and 40 female (20 HCR and 20 LCR) rats were randomly assigned to 3 weeks of activity wheel exposure or sedentary conditions without wheel access. After 3 weeks of activity-wheel running, rats were decapitated and brains were extracted. Coronal sections were analyzed utilizing in situ hybridization histochemistry for enkephalin (ENK) mRNA in the ventral striatum., Results: HCR rats expressed less ENK than LCR rats in the nucleus accumbens among females (p<0.01) and in the olfactory tubercle among both females (p<0.05) and males (p<0.05). There was no effect of wheel running on ENK mRNA expression., Conclusion: Line differences in ENK expression in the olfactory tubercle, and possibly the nucleus accumbens, partly explain divergent wheel-running behavior. The lower striatal ENK in the HCR line is consistent with enhanced dopaminergic tone, which may explain the increased motivation for wheel running observed in the HCR line., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or received a single high, dose of the β-carboline FG7142 (inverse agonist at the benzodiazepine receptor site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the last 10d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test battery produced intense avoidance and immobility consistent with an anxiety-like response. However, exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our data support a role for galanin in the beneficial consequences of wheel running., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We evaluated levels of exercise-induced brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) within the hippocampal formation in rats selectively bred for 1) high intrinsic (i.e., untrained) aerobic capacity (High Capacity Runners, HCR), 2) low intrinsic aerobic capacity (Low Capacity Runners, LCR), and 3) unselected Sprague-Dawley (SD) rats with or without free access to running wheels for 3 weeks. The specific aim of the study was to determine whether a dose-response relationship exists between cumulative running distance and levels of BDNF mRNA. No additional treatments or behavioral manipulations were used. HCR, LCR, and SD rats were grouped by strain and randomly assigned to sedentary or activity (voluntary access to activity wheel) conditions. Animals were killed after 21 days of exposure to the assigned conditions. Daily running distances (mean ± standard deviation meters/day) during week three were: HCR (4726 ± 3220), SD (2293 ± 3461), LCR (672 ± 323). Regardless of strain, levels of BDNF mRNA in CA1 were elevated in wheel runners compared to sedentary rats and this difference persisted after adjustment for age (p=0.040). BDNF mRNA was not affected by intrinsic aerobic capacity and was not related to total running distance. The results support that BDNF mRNA expression is increased by unlimited access to activity wheel running for 3 weeks but is not dependent upon accumulated running distance., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Studies in both humans and rodents suggest that exercise can be neuroprotective, but the mechanisms by which this occurs are still poorly understood. Three weeks of voluntary, physical activity in rats upregulates prepro-galanin messenger RNA levels in the locus coeruleus. Galanin is a neuropeptide extensively coexisting with norepinephrine that decreases neuronal hyperexcitability both in vivo and in vitro. Thus, exercise may diminish neural hyperexcitability through a galaninergic mechanism. The current experiments tested whether voluntary activity wheel running would protect against kainic acid-evoked seizures and whether galaninergic signaling is a necessary factor in this protection. In experiment 1, rats were given access to running wheels or remained sedentary for three weeks. After this period, rats received an intraperitoneal (i.p.) injection of 0, 7, 10 or 14 mg/kg kainic acid. Exercise decreased the severity of or eliminated seizure behaviors and hippocampal c-fos expression induced by kainic acid. In experiment 2, exercising or sedentary rats were injected intracerebroventricularly (i.c.v.) with 0.2 or 0.4 microg of kainic acid following either an injection of M-40 (a galanin receptor antagonist) or saline. Exercise decreased kainic acid-induced seizures at the 0.2 microg dose, and M-40 (6 nmol) decreased this effect. In contrast, there were no detectable differences between exercising and sedentary rats in behavior at the 0.4 microg dose. The results suggest that the protective effects of exercise against seizures are at least partially mediated by regulation of neural excitability through a process involving galanin.

The syndrome of behavioral, physiological, and neurochemical changes caused by ablation of the olfactory bulbs (OBX) in rats serves as a reliable and well-validated model of depression. Previous experiments have demonstrated that OBX leads to increased expression of the preproenkephalin (ENK) gene in the olfactory tubercle (OT) portion of the ventral striatum in rats. The aim of the present experiments was to investigate the role of OBX-induced ENK overexpression in the OT in the behavioral abnormalities exhibited by bulbectomized rats. A recombinant herpes virus carrying human preproENK cDNA was used to manipulate ENK gene expression in the OT of bulbectomized and sham-operated rats. Motivational deficits were assessed by the sucrose preference test, and 'agitation-like' behaviors were measured with the novel open field and footshock-induced freezing tests. ENK gene transfer in sham-operated rats mimicked some of the effects of OBX; it decreased freezing behavior in response to mild footshock and produced behavioral activation in the open field. In another experiment, virally mediated ENK gene transfer into the OT of intact rats decreased footshock-induced freezing, and this effect was reversed by naltrexone administration. PreproENK gene transfer into the OT did not produce analgesic effects in the tail-flick test. No effects on freezing behavior were observed following preproENK gene transfer into the frontal cortex. An additional experiment revealed that naltrexone administration attenuated the OBX-induced abnormality in freezing behavior. The results indicate that overexpression of the preproENK gene in the ventral striatum may mediate the 'agitation-like' behavior exhibited by bulbectomized rats.

We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited.

Previous research has demonstrated that the density of peripheral benzodiazepine receptors (PBR) in rat kidney rapidly drops following exposure to 80 min of stress. The present experiments examined the contribution of the central and autonomic nervous systems in mediating this effect. Ibotenic acid lesions of the amygdaloid central nucleus (ACe), but not the lateral and basolateral amygdala, diminished the magnitude of the reduction in renal PBR binding caused by stress. Pretreating rats with methyl-scopolamine also inhibited the response of the PBR to stress. Adrenergic blockade with nadolol was ineffective. In order to test whether the PBR was under direct or indirect neural control during stress, unilateral renal denervation was performed. The stress-induced reduction in PBR binding persisted in denervated kidneys revealing that any neural control over the PBR that might exist must be indirect. Together the results suggest that the CNS may be involved in regulating the PBR during stress through the activation of intermediate, possibly hormonal, factors. The involvement of the central nervous system in the modulation of the PBR indicates the relevance of the PBR to physiological adaptations to stress.

Exposure to environmental stress causes changes in the binding of [3H]Ro 5-4864 to peripheral benzodiazepine receptors (PBRs). The influence of the central nervous system (CNS) in these stress-induced modifications is unclear. The present study examined whether pretreatment with a dose-response regimen of sodium pentobarbital would impact the stress-induced reduction in renal PBR. Administration of either a sedative/ataxic (20 mg/kg) or hypnotic (60 mg/kg) dose of pentobarbital prior to stress blocks the stress-induced decrease of [3H]Ro 5-4864 binding to renal PBR in rat. These findings suggest that higher-order, supraspinal mechanisms play a critical role in marshalling the renal PBR changes in response to stress.

This work investigates the production of prostaglandin E2 (PGE2), a well known modulator for the suppression of immune cells, by pre-implantation human conceptuses from the 4-cell stage to the hatched blastocyst and by cumulus oophorus cells, these being obtained from an IVF/ET program. Cumulus cell complexes cultured for 48 h produced considerable amounts of PGE2, necessitating complete removal of their influence on the conceptus cultures. All stages of the human conceptus studied produced PGE2 during 48-h cultures, the greatest amounts from late blastocysts, and from those cultured in media containing bovine serum albumin rather than human donor serum. Indomethacin-treated control blastocysts confirmed the synthesis and release from the human conceptuses. The production of PGF2a from human blastocysts could not be demonstrated.