Food Deprivation, Body Weight Loss and Anxiety-Related Behavior in Rats

In behavioral studies, food deprivation protocols are routinely used to initiate or maintain motivational states that are required in a particular test situation. However, there is limited evidence as to when food deprivation compromises animal welfare. This study investigated the effects of different lengths of food deprivation periods and restricted (fixed-time) feeding on body weight loss as well as anxiety-related and motivated behavior in 5–6 month old male and female Wistar rats. The observed body weight loss was not influenced by sex and ranged between 4% (16 h deprivation) to approximately 9% (fixed-time feeding). Despite significant body weight loss in all groups, the motivation to eat under the aversive test conditions of the modified open field test increased only after 48 h of food deprivation. Long-lasting effects on anxiety as measured in the elevated plus maze test 24 h after refeeding have not been observed, although fixed-time feeding could possibly lead to a lasting anxiogenic effect in female rats. Overall, female rats showed a more anxiolytic profile in both tests when compared to male rats. Despite these sex differences, results suggest that food deprivation is not always paralleled by an increased motivation to feed in a conflict situation. This is an important finding as it highlights the need for tailored pilot experiments to evaluate the impact of food deprivation protocols on animals in regard to the principles of the 3Rs introduced by Russell and Burch. View Full-Tex

Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

Rationale Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). Objective Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. Methods The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. Results Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. Conclusions The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs

The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma

Background. Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC. Methods. Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group. Results. Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0–5] vs. 1 [0–3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5–50] vs. 23 [8–164]; p = 0.013), but not OS, compared with the nonSRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT. Conclusions. SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS

Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation

Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/ glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT1AR activation might predispose to a high anxious phenotype and an impaired stress coping behavior.Funding sources: This research was supported by Spanish Ministry of Economy and Competitiveness (SAF2011-25020 and SAF2015-67457-R), Instituto de Salud Carlos III (FIS Grant PI13-00038) co-funded by the European Regional Development Fund (‘A way to buildEurope’) and Centro de Investigacion Biomedica en Red de Salud Mental(CIBERSAM)

Die Bedeutung des extrazellulären Matrixproteins Reelin für kognitive Funktionen der Ratte

Reelin is critically involved in neuronal migration processes during embryonic development. Additionally, a loss of brain reelin is associated with schizophrenia and there is evidence that the protein acts as a modulator in aspects of learning and memory. However, little is known about the influence of reelin on behavioural and cognitive functions in vivo. The present study investigated the effects of an antisense elicited, temporary reelin-knockdown in the medial prefrontal cortex (mPFC) on rats' behaviour. A local reelin-knockdown during puberty or adulthood induced a significant sensorimotor gating deficit as well as an explicit impairment of spatial working memory following pubertal antisense injections. Western blot analyses showed a distinct and highly sensitive reelin-knockdown in the mPFC. Thus, these findings might be relevant for the understanding of (1) the pathophysiology of schizophrenia as well as (2) the role of reelin as a neurotrophic modulator of synaptic efficacy and cognitive functions

Impairment of sensorimotor gating and working memory after temporary reelin-knockdown in the mPFC of pubertal or adult rats

Reelin is critically involved in neuronal migration processes during embryonic development. Additionally, a loss of brain reelin is associated with schizophrenia and there is evidence that the protein acts as a modulator in aspects of learning and memory. However, little is known about the influence of reelin on behavioural and cognitive functions in vivo. The present study investigated the effects of an antisense elicited, temporary reelin-knockdown in the medial prefrontal cortex (mPFC) on rats' behaviour. A local reelin-knockdown during puberty or adulthood induced a significant sensorimotor gating deficit as well as an explicit impairment of spatial working memory following pubertal antisense injections. Western blot analyses showed a distinct and highly sensitive reelin-knockdown in the mPFC. Thus, these findings might be relevant for the understanding of (1) the pathophysiology of schizophrenia as well as (2) the role of reelin as a neurotrophic modulator of synaptic efficacy and cognitive functions

The impact of signet ring cell differentiation on outcome in patients with esophageal and gastroesophageal junction adenocarcinoma

Background: Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC. Methods: Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group. Results: Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0–5] vs. 1 [0–3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5–50] vs. 23 [8–164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT. Conclusions: SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS

Enhanced Stress Response in 5‑HT_1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation

Postsynaptic 5-HT_1A receptors (5-HT_1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT_1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT_1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT_1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT_1AR activation might predispose to a high anxious phenotype and an impaired stress coping behavior

Inspiration Geschichte : Publikation der Arbeitsgemeinschaft des Kunsthandwerks Hamburg e.V.

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