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Severe feather pecking (SFP) in chickens is a detrimental behaviour with possibly neurochemical deficits at its base. Recent neurological studies depicted conflicting results on the role of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) in the development and display of feather pecking. We studied brain monoamine levels and behaviour in domestic chickens divergently genetically selected on feather pecking behaviour, the Low Feather Pecking (LFP) and High Feather Pecking (HFP) lines, both at a young age and when adult, to elucidate the role of 5-HT and DA in feather pecking. Also pecking behaviour and the behavioural response to challenging test situations was determined. At 8 weeks of age, HFP had lower 5-HT and DA turnover in several brain areas than LFP, whereas these differences had disappeared or were even reversed at 25 weeks of age. Line differences in central monoamine activity were found both in emotion-regulating and motor-regulating areas. As expected from previous generations, HFP exceeded LFP in most types of pecking at other birds, including severe feather pecking. Furthermore, HFP responded more actively in most behavioural tests conducted, and seem more impulsive or (hyper)active in their way of coping with challenges. This paper shows different developmental trajectories of the neurochemical systems (5-HT and DA) for chickens divergently selected on feather pecking behaviour, and a remarkable reversion of differences in monoamine activity at a later stage of life. Whether this is a cause or consequence of SFP needs further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically diverse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Severe feather pecking (FP) is a detrimental behavior causing welfare problems in laying hens. Divergent genetic selection for FP in White Leghorns resulted in strong differences in FP incidences between lines. More recently, it was shown that the high FP (HFP) birds have increased locomotor activity as compared to hens of the low FP (LFP) line, but whether these lines differ in central serotonin (5-hydroxytryptamine, 5-HT) release is unknown. We compared baseline release levels of central 5-HT, and the metabolite 5-HIAA in the limbic and prefrontal subcomponents of the caudal nidopallium by in vivo microdialysis in adult HFP and LFP laying hens from the ninth generation of selection. A single subcutaneous d-fenfluramine injection (0.5 mg/kg) was given to release neuronal serotonin in order to investigate presynaptic storage capacity. The present study shows that HFP hens had higher baseline levels of 5-HT in the caudal nidopallium as compared to LFP laying hens. Remarkably, no differences in plasma tryptophan levels (precursor of 5-HT) between the lines were observed. d-fenfluramine increased 5-HT levels in both lines similarly indirectly suggesting that presynaptic storage capacity was the same. The present study shows that HFP hens release more 5-HT under baseline conditions in the caudal nidopallium as compared to the LFP birds. This suggests that HFP hens are characterized by a higher tonic 5-HT release., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow's milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-Fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Feather pecking (FP) in laying hens may cause mortality due to cannibalism. Novel breeding methods using survival days of group-housed siblings allow for the genetic selection of laying hens with low mortality (LML: low mortality line) due to cannibalism. Previous studies have demonstrated less fear-related behavior and also less FP in LML hens compared to CL. Selection also caused changes in locomotor behavior in an open field. It is unknown, however, whether selection for low mortality affects central neurotransmitter levels. In this study, brain monoamine levels were measured in the dorsal thalamus, medial striatum, hippocampus and arcopallium of adult laying hens of both LML and CL using HPLC. Brain samples were collected after 5-min of manual restraint. The most prominent line differences were found in the arcopallium. Compared to CL, LML had lower levels of noradrenaline (NA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and tended to have lower levels of dopamine (DA), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Levels of serotonin (5-HT), 5-HT- and DA-turnover in this brain area were not affected by line. LML showed less fear-related behavior during the restraint than CL. These findings show that selection for low mortality in hens leads to changes of predominantly the dopaminergic system in the chicken's arcopallium, a forebrain somatomotor area also related to fear. This suggests a relationship between catecholamine functioning in this brain area and FP and cannibalistic behavior in chickens and underpins previously found relationships between FP, fear and high activity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Many patients with chronic inflammatory disorders have an abnormal high prevalence of major depression accompanied by elevated levels of tumor necrosis factor-α (TNF-α). We hypothesize that systemic TNF-α increases brain monoamine metabolism, which might induce anhedonia (i.e. a core symptom of major depression). The effect of an intraperitoneal TNF-α injection on extracellular monoamine and metabolite concentrations was investigated by in vivo microdialysis in the nucleus accumbens (NAc) of C57BL/6 mice. In another group, the effects of TNF-α on body weight and intracranial self-stimulation (ICSS) thresholds were measured. TNF-α reduced body weight and increased ICSS thresholds, suggesting a state of anhedonia. TNF-α did not affect serotonin levels, but increased its metabolite 5-HIAA in the NAc. Remarkably, TNF-α also increased the dopamine metabolite HVA, without affecting dopamine levels itself. These data concur with earlier findings that pro-inflammatory cytokines enhance serotonin transporter activity, and possibly also dopamine transporter activity in the brain. However, more research is needed to understand the precise molecular mechanisms by which TNF-α increases transporter activity and anhedonia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cyclooxygenase-2 (COX-2) is thought to play a role in the pathogenesis of various neurodegenerative disorders. However, clinical trials with COX-2 inhibitors have yielded contradictory results. In the present study we investigated whether COX-2 plays a role in the behavioral and cognitive impairments seen in olfactory bulbectomized rats. These impairments arise from neurodegenerative processes. First, we determined the time course of the OBX-induced behavioral (hyperactivity) and cognitive changes (fear memory) and how these correlate with changes in COX-2 mRNA expression in hippocampus. This experiment showed that the major impairments in behavior and cognition developed between Days 3 and 14 after OBX surgery, which correlated with changes in mRNA levels of COX-2, which increased at Days 7 and 14 after surgery but not anymore at day 28. In a subsequent experiment, rats were treated, starting two days before surgery, with the COX-2 inhibitor celecoxib (10 mg/kg, dissolved in drinking water) for 4 weeks. OBX-induced hyperactivity in the open field was normalized after 2 weeks of celecoxib treatment, but not longer after 4 weeks. Celecoxib partly rescued fear learning and memory deficits without affecting spatial memory. The effects of celecoxib on fear memory lasted up to 1 week posttreatment, but disappeared thereafter. Our results show that COX-2 plays a limited role (both in magnitude and time) in the development of the OBX syndrome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We examined juvenile social recognition and discrimination in mice with early post-natal onset, transgenic CRF over-expression (CRF-OE) and in their wild-type littermates (WT). CRF-OE mice showed enhanced social investigation during the first encounter, normal short-term and facilitated long-term social recognition memory, compared to WT. These results suggest that chronically elevated brain CRF tone may contribute in better remembering ethologically relevant and emotionally salient stimuli, such as social interaction., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In order to evaluate the influence of changes in affective state on light-enhanced startle, the effects of positive affect, induced by acute cocaine administration, and the effect of negative affect, induced by spontaneous cocaine withdrawal-induced anxiety, were studied. Acute cocaine administration decreased LES, whereas withdrawal from chronic cocaine administration exacerbated LES 24h after withdrawal, an effect indicative of increased anxiety. This exacerbated LES was reduced, but not back to normal, 4 days after withdrawal. The finding that both cocaine-induced positive and negative affect can be detected in LES, suggests that this may be a valuable tool in studying affect regulation in rodents., ((c) 2010 Elsevier B.V. All rights reserved.)

Affective startle modulation is used to study emotional reactivity in humans, and blunted affective startle modulation has been reported in depressed patients. To determine whether blunted affective startle modulation is also a common feature in animal models for affective disorders, light-enhanced startle was studied in three models: inescapable foot shock (IFS), repeated restraint stress (RRS) and olfactory bulbectomy (OBX). In addition, prepulse inhibition was studied in these models. Light-enhanced startle was blunted following IFS and OBX and RRS decreased overall startle responding. Prepulse inhibition, however, was unaffected. These findings indicate that induction models for affective disorders may be associated with long term effects on affective startle modulation. The lack of changes in sensory motor gating suggests that these changes can be ascribed to alterations in emotional reactivity. In conclusion, our results indicate that the blunted affective startle modulation seen in animal models for affective disorders may be used to examine the mechanisms underlying altered emotional reactivity., (Copyright 2009 Elsevier B.V. All rights reserved.)

Impulsivity is an important symptom of many psychiatric disorders, and can be divided into two subtypes: response inhibition deficits and delay aversion. In the present study, we investigated the relationship between delay aversion and response inhibition, both to each other and to locomotion, extinction of conditioned responses, sexual behaviour, and aggressive behaviour. To that end, we quantified the behaviour of 24 rats in several tests. To measure response inhibition, rats were trained in a stop-signal task. In this operant task, rats were rewarded food if they inhibited execution of a response after presentation of an audible stop-signal. Delay aversion was measured in an operant task in which rats made a choice between a small, immediately available reward and a large reward available after a delay. The results showed that delay aversion and response inhibition were independent. Responses during extinction and various measures of aggressive behaviour were positively correlated to delay aversion. The speed of go-trials in the stop-task was correlated to non-aggressive behaviour. We conclude that the role of response inhibition in various behaviours is small, but delay aversion in particular contributes to several other behaviours, such as aggressive behaviour and extinction.

This study was based on the higher prevalence of anxiety disorders in women than in men, and on the finding that early adverse experiences are a major risk factor for the development of anxiety disorders later in life. The object of this study was to investigate in rats, the sensitivities of the light-enhanced startle (LES) and fear-potentiated startle (FPS) paradigms to sex differences and to determine the effects of maternal separation (MS) on the baseline startle magnitude and potentiated startle response in these paradigms. Pups in the MS group were separated daily from their mother for 180 min/day from postnatal day 2 (PND2) to PND14. Control litters remained undisturbed. The adult male and female progeny were tested in the FPS and LES. As predicted, females showed a significantly greater potentiation of startle than males in the FPS, and a strong trend towards greater startle potentiation in the LES. Contrary to predictions, MS had no effect on startle potentiation in the FPS and severely disrupted LES in female, but not male rats. The observed sex differences add to the validity of the FPS and LES as animal paradigms of fear and anxiety. The findings indicate that these paradigms can be used to study the biological basis of sex differences in fear and anxiety. In contrast, the effects of MS on startle potentiation argue against the idea that MS provides a robust model for the predicted influences of early adverse effects on these startle potentiation measures of fear and anxiety.

Previous studies with mice lacking 5-HT(1A) (1AKO) and 5-HT(1B) (1BKO) receptors in hippocampus-dependent learning and memory paradigms, suggest that these receptors play an important role in learning and memory, although their precise role is unclear. In the present study, 1AKO and 1BKO mice were studied in operant behavioural paradigms of decision making and response inhibition, to further study the putative involvement of these receptors in prefrontal cortex-dependent learning and memory. Moreover, because 1AKO mice have been shown to exhibit an antidepressant-like phenotype and 1BKO mice to be more impulsive in ethological studies, mice were trained in a differential-reinforcement-of-low-rates (DRL) procedure. Overall, results indicate that 1AKO and 1BKO mice display subtle differences in operant paradigms of decision making and response inhibition compared to wild type (WT) mice. In addition, when responding under a DRL 36-s schedule had stabilised, 1BKO mice showed a phenotype indicative of increased impulsivity, whereas 1AKO mice did not differ from WT mice. In conclusion, 5-HT(1B) receptors appear to play an important role in impulsivity and a minor role in prefrontal cortex-dependent learning and memory as shown by the results obtained in serial reversal learning and extinction. In contrast, 5-HT(1A) receptors appear to be involved in facilitation of autoshaping, but their role in impulsivity and prefrontal cortex-dependent learning and memory appears to be limited.

It has been shown before that unconditioned footshocks can augment the acoustic startle response in rats. In the present study, male mice of two strains, C57Bl/6N and BALB/c, were compared with regard to footshock-induced sensitization of the acoustic startle response. Presentation of footshocks did not affect the acoustic startle response in C57Bl/6N mice, while in contrast, footshock-induced sensitization was apparent in the BALB/c strain. Shocked C57Bl/6N mice, but not BALB/c mice, displayed robust conditioning to the startle context when re-tested the next day. These findings indicate that mice may exhibit footshock-induced sensitization of the acoustic startle response, but that the effects of footshocks on the acoustic startle are strain- and time-dependent.

To investigate whether the hyperreactivity to mild environmental and novel stimuli in 5-HT1B receptor knockout (1BKO) mice, as suggested by measures of exploratory, aggressive, and impulsive behaviors, can be extended to phasic stimuli, 1BKO and wildtype mice were tested in acoustic startle reactivity and plasticity paradigms, including habituation, prepulse inhibition, and footshock-induced sensitization of the startle response. Furthermore, we compared 5-HT1A receptor knockout (1AKO) and 1BKO mice to further test the suggested opposite behavioral profiles in these two genotypes. Results show that startle reactivity and footshock-induced sensitization was reduced in 1BKO mice, with no changes in habituation or PPI. In contrast, 1AKO mice did not differ from WT mice in any of the measures. These results indicate that an absence of 5-HT1B receptors, but not of 5-HT1A receptors, affects the modulation of startle reactivity and footshock-induced sensitization, without influencing startle plasticity. Moreover, this study suggests that 1AKO mice display a distinct, but not opposite behavioral profile from 1BKO mice. Furthermore, it is concluded that the hyperreactivity in 1BKO mice cannot be generalized to all stimuli, including the startling stimuli used in this study, but is probably restricted to mild environmental stimuli only.

Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying ejaculation. We describe here the neurophysiology and the peripheral neuroanatomy of ejaculation and provide a review of the involvement of serotonin in the central nervous system in relation to serotonergic nuclei and their projections. A hypothesis of the role of 5-HT1A and 5-HT2C receptors in premature ejaculation is postulated.

Effects of bilateral infusions of cholinergic drugs into the dorsal part of the medial prefrontal cortex (dmPFC) on performance in a delayed conditional discrimination (DCD) task were examined in rats. Scopolamine dose-dependently impaired performance. No delay-dependent effect was found indicating that scopolamine did not specifically affect working memory (WM). Physostigmine alone induced a slight improvement of DCD performance independent of delay and co-administration of physostigmine with scopolamine attenuated the scopolamine-induced impairment of DCD performance. Infusion of the muscarinic M2 antagonist AQRA-471, the M3 antagonist 4-DAMP and the mixed M1-M3 antagonist UH-AH 37 did not affect performance in the DCD task, suggesting that the effect of scopolamine is not mediated by a single muscarinic receptor subtype. The results furthermore indicate that the cholinergic system in the dmPFC does not play a specific role in WM processes in the DCD task. Furthermore, the results suggest that the dmPFC cholinergic system plays a role in the attentional processes involved in the DCD task.

Adult male Wezob-rats were bilaterally lesioned in either the medial anterior hypothalamic area or the mammillary bodies. The behaviour of these animals when confronted with a male intruder within their own territory, was observed and recorded before and after lesioning and compared with the behaviour of sham-operated animals. Anterior hypothalamic lesions, including large parts of the anterior hypothalamus, the rostral part of the ventromedial hypothalamic nucleus and smaller caudal parts of the preoptic area, led to strong increases in defensive behaviour. This included a decreased tendency to investigate the intruder and an exaggerated defensive reaction when approached by the intruder. Ingestive behaviour and bodyweight were enhanced. Mammillary body lesions, including large parts of the ventral and dorsal premammillary nucleus, the caudal part of the arcuate nucleus, the medial mammillary nucleus, the posterior mammillary nucleus, the supramammillary peduncle and closely surrounding areas, led to a marked increase in offensive behaviour. This was characterized by high levels of initiatives and aggression towards an intruder. It is suggested that two distinct neural substrates exist in the medial hypothalamus, which normally modulate defensive (anterior medial hypothalamus) or offensive (posterior medial hypothalamus) aspects of intermale aggression.