Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior

The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress-related anxiety disorders

Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits

Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mic

Identification of a novel gene regulating amygdala-mediated fear extinction.

Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders

Regular Exposure to Cowbells Affects the Behavioral Reactivity to a Noise Stimulus in Dairy Cows

In alpine regions, cows are often equipped with bells during pasture season to ensure that farmers can locate them. Constant exposure to the chime of a bell may affect cows’ acoustic perception in general. The aim of this study is to test whether routine bell exposure affects the reactivity to a noise stimulus and might be associated with hearing impairment in cows. For the assessment, behavioral and cardiac indicators were used as indirect measures of hearing capacity. Cows that were either used to wearing a bell or not were exposed to a playback of low and high amplitude (=varying loudness). In addition, we tested whether wearing earplugs, mimicking hearing impairment, reduced the cows’ reactivity toward the playback. On 24 farms, half of them routinely using cowbells, 96 Brown Swiss cows were tested in a 2 × 2 factorial cross-over design (65 or 85 dB, without or with earplugs) in a balanced order. The effects of bell experience, amplitude, and earplugs on the latency to the first behavioral and cardiac response to a 5-s playback were analyzed using linear mixed-effects models, considering dependencies within the data set. Cows reacted faster without earplugs and when they were exposed to 85 dB compared with 65 dB. The proportion of cows leaving the feeding rack after onset of the playback was reduced by bell experience and earplugs and was increased when exposed to 85 dB compared with 65 dB. Exposure without earplugs to 85 dB but not to 65 dB increased heart rate. Heart rate and heart rate variability indicated increased sympathetic activation during the exposure to 85 dB compared with 65 dB. In general, behavioral and cardiac indicators did not indicate severe hearing impairment due to routine bell exposure. The 85-dB stimulus increased arousal and avoidance compared with the 65-dB stimulus, with bell experience and earplugs leading to a general decrease in avoidance of the stimulus. This may reflect an altered acoustic perception of the playback stimulus in dairy cows that are routinely exposed to bells

Regular Exposure to Cowbells Affects the Behavioral Reactivity to a Noise Stimulus in Dairy Cows

In alpine regions, cows are often equipped with bells during pasture season to ensure that farmers can locate them. Constant exposure to the chime of a bell may affect cows’ acoustic perception in general. The aim of this study is to test whether routine bell exposure affects the reactivity to a noise stimulus and might be associated with hearing impairment in cows. For the assessment, behavioral and cardiac indicators were used as indirect measures of hearing capacity. Cows that were either used to wearing a bell or not were exposed to a playback of low and high amplitude (=varying loudness). In addition, we tested whether wearing earplugs, mimicking hearing impairment, reduced the cows’ reactivity toward the playback. On 24 farms, half of them routinely using cowbells, 96 Brown Swiss cows were tested in a 2 × 2 factorial cross-over design (65 or 85 dB, without or with earplugs) in a balanced order. The effects of bell experience, amplitude, and earplugs on the latency to the first behavioral and cardiac response to a 5-s playback were analyzed using linear mixed-effects models, considering dependencies within the data set. Cows reacted faster without earplugs and when they were exposed to 85 dB compared with 65 dB. The proportion of cows leaving the feeding rack after onset of the playback was reduced by bell experience and earplugs and was increased when exposed to 85 dB compared with 65 dB. Exposure without earplugs to 85 dB but not to 65 dB increased heart rate. Heart rate and heart rate variability indicated increased sympathetic activation during the exposure to 85 dB compared with 65 dB. In general, behavioral and cardiac indicators did not indicate severe hearing impairment due to routine bell exposure. The 85-dB stimulus increased arousal and avoidance compared with the 65-dB stimulus, with bell experience and earplugs leading to a general decrease in avoidance of the stimulus. This may reflect an altered acoustic perception of the playback stimulus in dairy cows that are routinely exposed to bells.Peer Reviewe

Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease

Appl. microbiol. biotechnol.

The concept of wine complexity has gained considerable interest in recent years, both for wine consumers and wine scientists. As a consequence, some research programs concentrate on the factors that could improve the perceived complexity of a wine. Notably, the possible influence of microbiological factors is particularly investigated. However, wine complexity is a multicomponent concept not easily defined. In this review, we first describe the actual knowledge regarding wine complexity, its perception, and wine chemical composition. In particular, we emphasize that, contrary to expectations, the perception of wine complexity is not related to wine chemical complexity. Then, we review the impact of wine microorganisms on wine complexity, with a specific focus on publications including sensory analyses. While microorganisms definitively can impact wine complexity, the underlying mechanisms and molecules are far from being deciphered. Finally, we discuss some prospective research fields that will help improving our understanding of wine complexity, including perceptive interactions, microbial interactions, and other challenging phenomena

Altered sleep intensity upon DBS to hypothalamic sleep-wake centers in rats

Deep brain stimulation (DBS) has been scarcely investigated in the field of sleep research. We hypothesize that DBS onto hypothalamic sleep- and wake-promoting centers will produce significant neuromodulatory effects and potentially become a therapeutic strategy for patients suffering severe, drug-refractory sleep-wake disturbances. We aimed to investigate whether continuous electrical high-frequency DBS, such as that often implemented in clinical practice, in the ventrolateral preoptic nucleus (VLPO) or the perifornical area of the posterior lateral hypothalamus (PeFLH), significantly modulates sleep-wake characteristics and behavior. We implanted healthy rats with electroencephalographic/electromyographic electrodes and recorded vigilance states in parallel to bilateral bipolar stimulation of VLPO and PeFLH at 125 Hz and 90 µA over 24 h to test the modulating effects of DBS on sleep-wake proportions, stability and spectral power in relation to the baseline. We unexpectedly found that VLPO DBS at 125 Hz deepens slow-wave sleep (SWS) as measured by increased delta power, while sleep proportions and fragmentation remain unaffected. Thus, the intensity, but not the amount of sleep or its stability, is modulated. Similarly, the proportion and stability of vigilance states remained altogether unaltered upon PeFLH DBS but, in contrast to VLPO, 125 Hz stimulation unexpectedly weakened SWS, as evidenced by reduced delta power. This study provides novel insights into non-acute functional outputs of major sleep-wake centers in the rat brain in response to electrical high-frequency stimulation, a paradigm frequently used in human DBS. In the conditions assayed, while exerting no major effects on the sleep-wake architecture, hypothalamic high-frequency stimulation arises as a provocative sleep intensity-modulating approach