Behavioral and neural mechanisms of face-specific attention during goal-directed visual search.

Goal-directed visual attention is a fundamental cognitive process that enables animals to selectively focus on specific regions of the visual field while filtering out irrelevant information. However, given the domain specificity of social behaviors, it remains unclear whether attention to faces versus non-faces recruits different neurocognitive processes. In this study, we simultaneously recorded activity from temporal and frontal nodes of the attention network while macaques performed a goal-directed visual search task. V4 and inferotemporal (IT) visual category-selective units, selected during cue presentation, discriminated fixations on targets and distractors during the search, but were differentially engaged by face and house targets. V4 and IT category-selective units also encoded fixation transitions and search dynamics. Compared to distractors, fixations on targets reduced spike-LFP coherence within the temporal cortex. Importantly, target-induced desynchronization between the temporal and prefrontal cortices was only evident for face targets, suggesting that attention to faces differentially engaged the prefrontal cortex. We further revealed bidirectional theta influence between the temporal and prefrontal cortices using Granger causality, which was again disproportionate for faces. Finally, we showed that the search became more efficient with increasing target-induced desynchronization. Together, our results suggest domain specificity for attending to faces and an intricate interplay between visual attention and social processing neural networks.

Distinct attentional profile and functional connectivity of neurons with visual feature coding in the primate brain.

Visual attention and object recognition are two critical cognitive functions that significantly influence our perception of the world. While these neural processes converge on the temporal cortex, the exact nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and object feature coding by training macaques to perform a free-gaze visual search task using natural face and object stimuli. With a large number of units recorded from multiple brain areas, we discovered that units exhibiting visual feature coding displayed a distinct attentional response profile and functional connectivity compared to units not exhibiting feature coding. Attention directed towards search targets enhanced the pattern separation of stimuli across brain areas, and this enhancement was more pronounced for units encoding visual features. Our findings suggest two stages of neural processing, with the early stage primarily focused on processing visual features and the late stage dedicated to processing attention. Importantly, feature coding in the early stage could predict the attentional effect in the late stage. Together, our results suggest an intricate interplay between visual feature and attention coding in the primate brain, which can be attributed to the differential functional connectivity and neural networks engaged in these processes.

Hippocampal PKR/NLRP1 Inflammasome Pathway Is Required for the Depression-Like Behaviors in Rats with Neuropathic Pain.

The chronic neuropathic pain-associated psychiatric disorders have seriously disturbed the quality of patients' life, such as depression and anxiety. Neuroinflammation in the hippocampus plays an important role in the neuropathic pain-associated depressive and anxiety disorders, but the underlying mechanism has not been thoroughly elucidated to date. The Nod-like receptor protein (NLRP)-1 inflammasome, which controls the production of pro-inflammatory cytokines, was broadly involved in the neuroinflammation-related diseases. In the present study, we show that the NLRP1 inflammasome is significantly activated in the hippocampus of rats subjected to the chronic constriction injury (CCI)-induced neuropathic pain. Inhibiting the product of NLRP1 inflammasome not only attenuated the depression-like behaviors but also suppressed the production of mature IL-1ß in the hippocampus of CCI rats. The double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) has been recently shown to be a pivotal regulator for the activation of inflammasome. In the rats subjected to CCI neuropathic pain, the PKR was simultaneously activated in hippocampus. Functional inhibition of PKR suppressed the NLRP1 inflammasome activation and effectively attenuated the CCI-induced depression-like behaviors. These results indicate that the hippocampal PKR/NLRP1 inflammasome pathway play an important role in the development of the depressive behaviors after chronic neuropathic pain. Thus, interrupting this pathway might provide a novel therapeutic strategy for neuropathic pain-associated depressive disorders.

Ghrelin exhibited antidepressant and anxiolytic effect via the p38-MAPK signaling pathway in hippocampus.

Ghrelin, a peptide derived from stomach, is an endogenous ligand for growth hormone secretagogue receptor (GHSR). So far, the exact role of ghrelin in depression and anxiety is still being debated. The p38 mitogen-activated protein kinase (p38-MAPK) is known to be activated in response to various stress stimuli. Thus, we hypothesize that ghrelin has an antidepressant effect, to which the p38-MAPK signaling pathway significantly contributes. To test this hypothesis, chronic social defeat stress (CSDS) was used as a model of depression. We employed the adeno-associated virus-mediated siRNA approach to down-regulate GHSR expression in the hippocampus of mice in vivo. Both ghrelin and the p38 inhibitor, SB203580, were administered to identify the effect of ghrelin on depressive-like behavior of stressed mice and to better assess the role of the p38-MAPK signaling pathway in this process. We found that CSDS activated the endogenous ghrelin-GHSR in hippocampal neurons, which possibly resulted in opposing the formation of depression- and anxiety-like behaviors in mice. Furthermore, the p38-MAPK signaling pathway had an important role in the antidepressant effect of ghrelin. Therefore, we conclude that ghrelin may reduce CSDS-induced depression- and anxiety-like behaviors via inhibiting the p38-MAPK signaling pathway in hippocampal neurons of mice.

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors.

BACKGROUND: In recent years, proinflammatory cytokine interleukin-1ß (IL-1ß) was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor (P2X7R), a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1ß. Here, we investigated the role of P2X7R in the pathogenesis of depression. METHODS: Male Sprague-Dawley rats were subjected to chronic unpredictable stressors (CUS) for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1ß, and components and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze. RESULTS: Along with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1ß, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors. CONCLUSIONS: The activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.

Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents.

As a regulator of food intake, ghrelin also plays a key role in mood disorders. Previous studies reported that acute ghrelin administration defends against depressive symptoms of chronic stress. However, the effects of long-term ghrelin on rodents under chronic stress hasn't been revealed. In this study, we found chronic peripheral administration of ghrelin (5nmol/kg/day for 2 weeks, i.p.) could alleviate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress (CUMS). The depression-like behaviors were assessed by the forced swimming test (FST), and anxiety-like behaviors were assessed by the open field test (OFT) and the elevated plus maze test (EPM). Meanwhile, we observed that peripheral acylated ghrelin, together with gastral and hippocampal ghrelin prepropeptide mRNA level, were significantly up-regulated in CUMS mice. Besides, the increased protein level of growth hormone secretagogue receptor (GHSR) in hippocampus were also detected. These results suggested that the endogenous ghrelin/GHSR pathway activated by CUMS plays a role in homeostasis. Further results showed that central treatment of ghrelin (10µg/rat/day for 2 weeks, i.c.v.) or GHRP-6 (the agonist of GHSR, 10µg/rat/day for 2 weeks, i.c.v.) significantly alleviated the depression-like behaviors induced by CUMS in FST and sucrose preference test (SPT). Based on these results, we concluded that central GHSR is involved in the antidepressant-like effect of exogenous ghrelin treatment, and ghrelin/GHSR may have the inherent neuromodulatory properties against depressive symptoms.

[Effect of Electroacupuncture Stimulation of "Baihui" (GV 20) , etc. on Changes of Behavior and Plasma Ghrelin Content in Depression Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Baihui" (GV 20) + "Anmian" (EX-HN 16) and "Baihui" (GV 20) + "Zusanli" (ST 36) on behavior reactions and plasma ghrelin level in depression rats, so as to explore the correlation between its antidepressant effect and plasma ghrelin level. METHODS: A total of 45 SD rats were randomly divided into 5 groups: normal control, model, Baihui (GV 20) + Anmian (EX-HN 16), Baihui (GV 20) + Zusanli (ST 36) and medication (clomipramine) groups, with 9 rats in each group. The depression model (unpredictable chronic mild stresses, UC-MS) was established by giving the animals with higher temperature environment (45 °C, 5 min), forced ice-water swimming (0- 4 °C, 5 min) , day and night reversal environment (12 h), stroboflash stimulation (12 h), noisy stimulation (12 h), rocking-bed movement (30 min) and damp pad dwelling (6-24 h), etc. for 4 weeks. EA was applied to GV 20-EX-HN 16, and GV 20-ST 36 for 30 min once every other day for 4 weeks after modeling. For rats of the medication group, clomipramine (5 mg/kg) was given (i. p. ) once a day for 4 weeks after modeling. The forced swimming test, sucrose preference test and open field test were used to evaluate the rats depressive-like behavior. Plasma ghrelin content was assayed by ELISA. RESULTS: After exposure to UCMS for 4 weeks, the immobility time was significantly increased, and the struggling time was significantly decreased in the model group (P < 0.05, P < 0.01). In comparison with the model group, the immobility time levels were obviously decreased, while the struggling time and sucrose preference were markedly increased in the Baihui (GV 20) + Anmian (EX-HN 16) , Baihui (GV 20) + Zusanli (ST 36) and medication groups (P < 0.05, P < 0.01). No significant changes were found in the rearing times and total distance of open-field test (locomotor activity) and plasma ghrelin content among the 5 groups among all the groups (P > 0.05). No significant differences were found among the two EA and medication groups in the decreased immobility time and the increased struggling times and sucrose preference levels (P > 0.05). CONCLUSION: EA intervention can improve the depression rats' hopeless behavior of forced swimming test and anhedonia behavior (sucrose preference test) , which may be not correlated to plasma ghrelin level at the late-stages and the antidepressant effect of EA intervention.

Electroacupuncture promotes proliferation of amplifying neural progenitors and preserves quiescent neural progenitors from apoptosis to alleviate depressive-like and anxiety-like behaviours.

The present study was designed to investigate the effects of electroacupuncture (EA) on depressive-like and anxiety-like behaviours and neural progenitors in the hippocampal dentate gyrus (DG) in a chronic unpredictable stress (CUS) rat model of depression. After being exposed to a CUS procedure for 2 weeks, rats were subjected to EA treatment, which was performed on acupoints Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan), once every other day for 15 consecutive days (including 8 treatments), with each treatment lasting for 30 min. The behavioural tests (i.e., forced swimming test, elevated plus-maze test, and open-field entries test) revealed that EA alleviated the depressive-like and anxiety-like behaviours of the stressed rats. Immunohistochemical results showed that proliferative cells (BrdU-positive) in the EA group were significantly larger in number compared with the Model group. Further, the results showed that EA significantly promoted the proliferation of amplifying neural progenitors (ANPs) and simultaneously inhibited the apoptosis of quiescent neural progenitors (QNPs). In a word, the mechanism underlying the antidepressant-like effects of EA is associated with enhancement of ANPs proliferation and preserving QNPs from apoptosis.

Electroacupuncture upregulates ERK signaling pathways and promotes adult hippocampal neural progenitors proliferation in a rat model of depression.

BACKGROUND: In this study, we investigate the proliferation of adult neural stem cells (NSCs) in a chronic unpredictable stress (CUS) rat model of depression, the effects of electroacupunture (EA) on depressive-like symptoms and the corresponding signaling pathways. METHODS: SD rats were subjected to 4 weeks of CUS to induce depressive-like behaviors. EA was performed at the Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan) acupoints. Rats were injected with BrdU and the brains were cut into sections. Double-labeling with BrdU/Sox2 and p-ERK/Nestin was performed to demonstrate the in vivo proliferation of adult NSCs in hippocampus and ERK activation in NSCs. Hippocampal microdialysates of different groups were collected to observe the in vitro effects on NSCs. RESULTS: After 8 treatments, EA generated a clear antidepressant effect on the stressed rats and promoted the NSC proliferation. ERK activation might be involved in the antidepressant-like effects of EA treatment. Hippocampal microdialysates from EA-treated stressed rats influenced NSCs to form larger neural spheres and exhibit higher p-ERK level in vitro, compared to the untreated stressed rats. Meanwhile, the antidepressant-like effects of EA involved contribution from both acupoint specificity and electrical stimulus. CONCLUSIONS: EA might interfere with the hippocampal microenvironment and enhance the activation of ERK signaling pathways. This could mediate, at least in part, the beneficial effects of EA on NSC proliferation and depressive-like behaviors.