Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Investigation of non-invasive focused ultrasound efficacy on depressive-like behavior in hemiparkinsonian rats.

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy. Following 6-hydroxydopamine (6-OHDA) lesion, akinesia-like immobility was assessed in the limb-use asymmetry test, and despair- and anhedonic-like behaviors were evaluated in the forced swim test and sucrose preference test, respectively. After, tyrosine hydroxylase immuno-staining was employed to visualize and quantify dopaminergic degeneration in the substantia nigra pars compacta, ventral tegmental area, and striatum. We found that PD rats exhibited akinesia-like immobility and > 90% reduction in tyrosine hydroxylase immuno-staining ipsilateral to the lesioned side. PD rats also demonstrated anhedonic-like behavior in the sucrose preference test compared to sham rats. No 6-OHDA lesion effect on immobility in the forced swim test limited conclusions about the efficacy of ultrasound on despair-like behavior. However, ultrasound improved anhedonic-like behavior in PD rats and this efficacy was sustained through the end of the 1-week recovery period. The greatest number of animals demonstrating increased sucrose preference was in the PD group receiving ultrasound. Our findings here are the first to posit that peripheral non-invasive focused ultrasound to the celiac plexus may improve anhedonia in PD with further investigation needed to reveal its potential for clinical applicability.

Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders.

Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0-6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B.

BACKGROUND: Bitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances. Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo. METHODS: To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues, multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique. A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes. Then, T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds. Perception to taste substance was also studied using two-bottle preference tests. RESULTS: We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique. Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice. But qRT-PCR results revealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice. With two-bottle preference tests, these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105. In addition, these mutant mice showed a loss of taste perception to quinine dihydrochloride, denatonium benzoate, and cucurbitacin B (CuB). Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception. CONCLUSIONS: These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

Comparison of reminder-preference test to difference and preference tests: An affective approach yielding d-prime results for sensory difference and preference.

Preserving the sensory characteristics of reformulated products is crucial for a successful market launch. This underscores the need for precise measurement of consumer perceptions regarding sensory differences and preferences. One approach to assess these aspects is through the utilization of the reminder-preference test, an affective difference-preference test employing the A-Not A with the reminder (A-Not AR) test design. This test measures sensory differences and preferences by employing a consolidated d' index rooted in signal detection theory and Thurstonian modeling. The aim of this study was to assess the efficacy of the reminder-preference test in measuring the degree of sensory differences and interpreting their relevance concerning consumer preference. To achieve this, the test was compared with both the A-Not AR difference test and the 2-alternative choice (2-AC) preference test. A lemon-lime-flavored carbonated drink and two types of reformulated samples were tested. Young female adult subjects were randomly divided into three groups. Each took one of the following three tests: the reminder-preference test, the reminder test of A-Not AR, or the 2-AC preference test. The reference framing in the reminder-preference and reminder tests was preceded by subjects watching the product's advertisement to assist them in framing evaluative criteria. This would also facilitate memorizing the perception of the reference product. Test sensitivity in reminder-preference matched reminder and 2-AC tests for sensory differences and preferences. Affective framing enhanced sensitivity to sensory differences resulting in a higher d' value of the sensory difference than the preference. From the results, it was possible to interpret that the measured sensory differences did not affect consumer preference. The test also illuminated brand marketing effects on preferences through branded reference comparison. Thus, the reminder-preference test shows potential as an efficient sensory method to measure sensory differences and the preference of consumers, while concurrently measuring the effects of marketing on the consumers. Therefore, it can assist in making efficient business decisions regarding product reformulations.

Antidepressant properties of voluntary exercise mediated by gut microbiota.

Although regular exercise has been reported to prevent depression, it has not been clarified whether the gut microbiota is involved in the factors that prevent depression through exercise. We investigated the effects of voluntary exercise on the gut microbiota and the prevention of depression-like behaviors using mice. C57BL/6 J male mice were subjected to 10 weeks of sedentary control or wheel running, then they were subjected to social defeat stress (SDS). Exercise attenuated that sucrose drinking was decreased by SDS treatment. Exercise increased the expression of Bdnf and decreased expression of Zo-1 and Claudin5 in the brain. Fecal Turicibacter, Allobaculum, and Clostridium sensu stricto, and propionate in the cecum were decreased by the exercise. Voluntary exercise-induced antidepressant properties might be partially caused by suppression of serotonin uptake into gut microbiota and increase the permeability of the blood-brain barrier via reduced propionate production.

Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents.

Anhedonia is described as a decreased ability to experience rewarding and enjoyable activities, a core symptom of major depressive disorder. The sucrose preference test (SPT) is a widely used and reliable behavioural test to assess anhedonia in rodents, based on a two-bottle choice paradigm. To date, different protocols are in use, inducing variability between researchers and hampering comparisons between studies. We performed a systematic review of the SPT protocols used in 2021 to identify the parameters in which they differ and their potential impact. We searched a total of four databases (PubMed, Scopus, Web of Science and Science Direct), from 1st January 2021 to 31st December 2021, and screened a total of 1066 articles. After screening by title and abstract, a total of 415 articles were included in this review. We extracted and analysed the different procedures used, the type of sweet solution and the habituation, deprivation, and testing protocols. The overall quality of the studies was considered very good, however, SPT protocols were extremely variable between studies with a total of 65 different habituation protocols and 104 combinations of food/water deprivation and preference testing duration. As the SPT is one of the most used tests to assess anhedonia in rodents, this work raises awareness of the great variability in SPT protocols being currently used. Furthermore, we call for standardization in the protocol used, and overall improvement of data reporting of methodologies and results, to increase the consistency between studies and allow a better comparison of results between different labs.

Rethinking data treatment: The sucrose preference threshold for anhedonia in stress-induced rat models of depression.

BACKGROUND: Exposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this method, as it measures a rat´s preference for a sweet solution as an indicator of its ability to experience pleasure. Typically, if stressed rats show a lower preference compared to unstressed rats, it is concluded they are experiencing stress-induced anhedonia. METHODS: While conducting a systematic review, we identified 18 studies that used thresholds to define anhedonia and to distinguish "susceptible" from "resilient" individuals. Based on their definitions, researchers either excluded "resilient" animals from further analyses or treated them as a separate cohort. We performed a descriptive analysis to understand the rationale behind these criteria. RESULTS: we found that the methods used for characterizing the stressed rats were largely unsupported. Many authors failed to justify their choices or relied exclusively on referencing previous studies. When tracing back the method to its origins, we converged on a pioneering article that, although employed as a universal evidence-based justification, cannot be regarded as such. What is more, through a simulation study, we provided evidence that removing or splitting data, based on an arbitrary threshold, introduces statistical bias by overestimating the effect of stress. CONCLUSION: Caution must be exercised when implementing a predefined cut-off for anhedonia. Researchers should be aware of potential biases introduced by their data treatment strategies and strive for transparent reporting of methodological decisions.

Transient Receptor Potential Ankyrin 1 in Taste Nerve Contributes to the Sense of Sweet Taste in Mice.

Transient receptor potential (TRP) channels play a significant role in taste perception. TRP ankyrin 1 (TRPA1) is present in the afferent sensory neurons and is activated by food-derived ingredients, such as Japanese horseradish, cinnamon, and garlic. The present study aimed to investigate the expression of TRPA1 in taste buds, and determine its functional roles in taste perception using TRPA1-deficient mice. In circumvallate papillae, TRPA1 immunoreactivity colocalised with P2X2 receptor-positive taste nerves but not with type II or III taste cell markers. Behavioural studies showed that TRPA1 deficiency significantly reduced sensitivity to sweet and umami tastes, but not to salty, bitter, and sour tastes, compared to that in wild-type animals. Furthermore, administration of the TRPA1 antagonist HC030031 significantly decreased taste preference to sucrose solution compared to that in the vehicle-treated group in the two-bottle preference tests. TRPA1 deficiency did not affect the structure of circumvallate papillae or the expression of type II or III taste cell and taste nerve markers. Adenosine 5'-O-(3-thio)triphosphate evoked inward currents did not differ between P2X2- and P2X2/TRPA1-expressing human embryonic kidney 293T cells. TRPA1-deficient mice had significantly decreased c-fos expression in the nucleus of the solitary tract in the brain stem following sucrose stimulation than wild-type mice. Taken together, the current study suggested that TRPA1 in the taste nerve contributes to the sense of sweet taste in mice.

Psychological dominant stressor modification to an animal model of depression with chronic unpredictable mild stress.

Background and Aim: Chronic unpredictable mild stress (CUMS) is a protocol widely used to create an animal model of depression with food deprivation, water deprivation, and physical-dominant stressors as routine procedures. However, human depression mainly involves psychological stressors and does not always involve a lack of food and water; thus, CUMS procedures should be modified accordingly. Therefore, this study aimed to create an animal model of depression, mainly focusing on a psychologically dominant stressor without food and water deprivation. Materials and Methods: The CUMS and control groups, respectively, received CUMS modification (psychologically dominant stressors without food and water deprivation) for 21 days. A 24-h sucrose preference test (SPT) was used to assess the successful creation of an animal model of depression. Daily food intake measurements, weekly weight monitoring, and weight gain calculations were performed. Either an independent sample t-test or the Mann-Whitney test was used. Results: Of the 42 rats included, 39 completed the study. Chronic unpredictable mild stress procedures for 21 days significantly reduced the SPT (p < 0.05), mean body weight (p < 0.05), and weekly weight gain (p < 0.05) in the CUMS group compared to the control group. However, the weekly average food intake did not statistically differ between the two groups. Conclusion: Psychological dominant CUMS modification to an animal model of depression resulted in lower SPT, body weight, and weekly weight gain in the CUMS group than in the control group.

Can a traditional partner preference test quantify monogamous behavior in captive coyotes?

Social monogamy is a unique social system exhibited by only 3-5% of mammalian taxa; however, all wild canid species exhibit this social system. Despite the high prevalence of social monogamy among canids, little is known about how they form selective social attachment relationships among non-kin. Thus, we aimed to quantify monogamous behavior in a highly ubiquitous canid, the coyote (Canis latrans). We adapted the three-chambered partner preference test, which was originally developed for prairie voles (Microtus ochrogaster), to assess social preference in mated pairs of captive coyotes at the USDA Predator Research Facility. We quantified monogamy-related behaviors, such as time spent in spatial proximity to a pair-mate versus a stranger. Our behavioral ethogram also included visual seeking, olfactory investigations, ears down, scent marking, and affiliative behavior. Test subjects showed significantly greater affiliative behavior toward their partner than toward a stranger. However, there was extremely high variability both within and between coyote pairs across behavioral measures. These data suggest the need for larger sample sizes when working with species with high individual variability, as well as the need for species- and facility-specific modifications to this testing paradigm and/or ethogram to better adapt it from its laboratory and rodent-based origins.

Plastic is a widely used and selectively chosen nesting material for pied flycatchers (Ficedula hypoleuca) in rural woodland habitats.

There is increasing concern about the burgeoning effects of discarded plastic on the earth's biodiversity. Quantifying the presence of plastic and other anthropogenic waste in the environment can be logistically and financially challenging, although it is possible that bird' nests can be used as bioindicators. Many birds in heavily modified terrestrial ecoystems, such as urban environments, incorporate plastic and other anthropogenic materials into their nests but our understanding of the presence of discarded plastic in nests in rural woodlands remains poor. Here, we show that plastic and other anthropogenic materials were present in 35 % of 325 pied flycatcher (Ficedula hypoleuca) nests from 17 rural woodlands throughout Great Britain, although the woodlands did vary in the amount of material incorporated into nests. Then, in an experimental test at one study site, where flycatchers were provided with a choice of two types of natural and two types of anthropogenic nest materials, they preferentially selected one natural and one anthropogenic material. In another test, the flycatchers were provided with plastic of four colours and overwhelmingly selected white and avoided orange, blue and yellow plastic. Although the flycatcher's selectivity for certain material types and colours preclude their nests being a reliable indicator of plastic in the environment, our study nonetheless demonstrates that bird species incorporate anthropogenic materials, such as plastic, into their nests in rural woodlands.

Determining the value of preferred goods based on consumer demand in a home-cage based test for mice.

From the preference of one good over another, the strength of the preference cannot automatically be inferred. While money is the common denominator to assess the value of goods in humans, it appears difficult at first glance to put a price tag on the decisions of laboratory animals. Here we used consumer demand tests to measure how much work female mice expend to obtain access to different liquids. The mice could each choose between two liquids, one of which was free. The amount of work required to access the other liquid, by contrast, increased daily. In this way, the value of the liquid can be determined from a mouse's microeconomic perspective. The unique feature is that our test was carried out in a home-cage based setup. The mice lived in a group but could individually access the test-cage, which was connected to the home-cage via a gate. Thereby the mice were able to perform their task undisturbed by group members and on a self-chosen schedule with minimal influence by the experimenter. Our results show that the maximum number of nosepokes depends on the liquids presented. Mice worked incredibly hard for access to water while a bitter-tasting solution was offered for free whereas they made less nosepokes for sweetened liquids while water was offered for free. The results demonstrate that it is possible to perform automated and home-cage based consumer demand tests in order to ask the mice not only what they like best but also how strong their preference is.

Material and food exploration by zoo-housed animals can inform cognition and enrichment apparatus design.

To robustly study zoo animal cognition and provide effective enrichment, we must provide animals with carefully designed apparatus made from appropriate (safe, attractive, practical) materials. However, all too often, this design phase is overlooked or omitted from the literature. We evaluated how a troop of 12 ring-tailed lemurs (Lemur catta) explored a range of novel materials and whole foods during outdoor social testing. These items were not intended to test cognition or be enriching; rather we viewed them as the potential "building blocks" from which to build our future apparatus. Lemurs preferred to explore wooden surfaces, but had no preference for manipulanda made from different materials. Large amounts of metal and untreated wood should be avoided in the future; metal produced too much heat and glare, and wood was damaged by biting/chewing. Lemurs used one or two hands to explore manipulanda, and simple touching was more common than twisting or pulling. However, lemurs were most likely to explore by smell than touch or by mouth. Social testing preserved "normal" conditions for the lemurs, including natural food stealing and scrounging in high- and low-ranking individuals, respectively. Our findings culminated in the development of a static, low-level cognitive task apparatus, constructed from modular plastic units. We encourage other researchers to report how they develop cognitive and enrichment apparatuses and consider a similar preference-testing approach.

Using Anticipatory Behavior as Preference Test in The Bottlenose Dolphin (Tursiops truncatus).

The preference tests have made a great contribution to promoting animal welfare. However, they are not always easily applicable and have some criticalities. Recently the anticipatory behavior has been used to detect the animals' preference. In this study, we attempted to investigate the relationship between preference and anticipatory behavior. To this end, we tested on a group of dolphins (Tursiops truncatus) whether, with anticipatory behavior, it is possible to distinguish the animals' preference for different objects and then use it as a preference test. Anticipatory behavior is exhibited throughout the animal kingdom, it is easy to induce and measure, and does not have the criticalities of other preference tests. Therefore, its use as preference test could facilitate the study of animals' preferences and contribute to the promotion of their welfare. Our results support the hypothesis of use anticipatory behavior as a preference test. In fact, dolphins have anticipated the arrival of objects highly preferred with a frequency three times higher than shown toward objects less preferred, providing further evidence of the correlation between anticipatory behavior and the animals' preference.

"The wrong tools for the right job": a critical meta-analysis of traditional tests to assess behavioural impacts of maternal separation.

RATIONALE: Unconditioned tasks in rodents have been the mainstay of behavioural assessment for decades, but their validity and sensitivity to detect the behavioural consequences of early life stress (ELS) remains contentious and highly variable. OBJECTIVES: In the present study, we carried out a meta-analysis to investigate whether persistent behavioural effects, as assessed using unconditioned procedures in rats, are a reliable consequence of early repeated maternal separation, a commonly used procedure in rodents to study ELS. METHODS: A literature search identified 100 studies involving maternally separated rats and the following unconditioned procedures: the elevated plus maze (EPM); open field test (OFT); sucrose preference test (SPT) and forced swim task (FST). Studies were included for analysis if the separation of offspring from the dam was at least 60 min every day during the pre-weaning period prior to the start of adolescence. RESULTS: Our findings show that unconditioned tasks are generally poor at consistently demonstrating differences between control and separated groups with pooled effect sizes that were either small or non-existent (EPM: Hedge's g = - 0.35, p = 0.01, OFT: Hedge's g = - 0.32, p = 0.05, SPT: Hedge's g = - 0.33, p = 0.21, FST: Hedge's g = 0.99, p = 0.0001). Despite considerable procedural variability between studies, heterogeneity statistics were low; indicating the lack of standardization in the maternal separation protocol was the not the cause of these inconsistent effects. CONCLUSIONS: Our findings indicate that in general, unconditioned tests of depression and anxiety are not sufficient to reveal the full behavioural repertoire of maternal separation stress should not be relied upon in isolation. We argue that more objective tasks that sensitively detect specific cognitive processes are better suited for translational research on stress-related disorders such as depression.

Pekin ducks are motivated to lay in their preferred nest substrate.

Nest design is one factor contributing to floor-laying in farmed poultry. We investigated: (i) if ducks (Anas platyrhynchos) prefer a particular nest substrate; and (ii) how important that preference is to them, indicated by stress-induced hyperthermia, egg albumen corticosterone, and behaviour. Twelve female ducks that were trained in a push-door task had temperature data loggers implanted. Preference testing identified the most and least preferred nest substrates between sawdust, astroturf, and hemp fibres. A behavioural demand test then required the ducks to use push-doors to access nests containing either the most or least preferred substrate. The preferred substrate door was loaded with increasing weight (0-120% of bodyweight, four nights per workload) and eventually blocked to prevent nest access. The least preferred substrate door remained unweighted. The overall rank order of substrate preferences was sawdust > hemp > astroturf. Six of the 12 birds pushed all workloads and attempted to push the blocked door. The area under the curve (AUC) of hyperthermia was larger when the preferred substrate door was blocked compared with 0%. The AUC did not differ between nights 2-4 of the blocked door compared with night 1. Egg albumen corticosterone was unaffected. We conclude that laying Pekin ducks prefer manipulatable nest substrates and accessing one is important enough to pay a cost. The results indicate that a manipulatable substrate should be provided to commercially farmed nesting ducks.

Assessment of commonly used tests in experimental depression studies according to behavioral patterns of rodents.

Considering the main factor that causes or triggers depression in humans is stress. Several stress factors are applied to form depression-like symptoms in rodents. Depression tests are used to analyze the nature and patterns of depression. Well-founded modeling and versatile evaluation of tests are necessary to investigate a hypothesis that is related to depression. It is impossible to model or test all aspects of depression in humans by using experimental animals. As a result, the aims of the study should be determined specifically in depression models. The correct interpretation of the tests that are suitable for these aims is indispensable for the reliability of the data. To achieve this goal, the biological basis of the depression-related behaviors of animals should be well known. In this review, model and test concepts related to depression are discussed and behavioral patterns of rodents are explained with several examples.

Potential Antioxidant Activity of Apigenin in the Obviating Stress-Mediated Depressive Symptoms of Experimental Mice.

This study aimed to examine the antidepressant properties of apigenin in an experimental mouse model of chronic mild stress (CMS). Three weeks following CMS, albino mice of either sex were tested for their antidepressant effects using the tail suspension test (TST) and the sucrose preference test. The percentage preference for sucrose solution and the amount of time spent immobile in the TST were calculated. The brain malondialdehyde (MDA) levels, catalase activity, and reduced glutathione levels were checked to determine the antioxidant potential of treatments. When compared to the control, animals treated with apigenin during the CMS periods showed significantly shorter TST immobility times. Apigenin administration raised the percentage preference for sucrose solution in a dose-dependent manner, which put it on par with the widely used antidepressant imipramine. Animals treated with apigenin displayed a significantly (p ˂ 0.05) greater spontaneous locomotor count (281) when compared to the vehicle-treated group (245). Apigenin was also highly effective in significantly (p ˂ 0.01) lowering plasma corticosterone levels (17 vs. 28 µg/mL) and nitrite (19 vs. 33 µg/mL) produced by CMS in comparison to the control group. During CMS, a high dose (50 mg/kg) of apigenin was given, which greatly increased the reduced glutathione level while significantly decreasing the brain's MDA and catalase activity when compared to the control group. As a result, we infer that high doses of apigenin may have potential antidepressant effects in animal models via various mechanisms.

The antidepressant effect of nucleus accumbens deep brain stimulation is mediated by parvalbumin-positive interneurons in the dorsal dentate gyrus.

The nucleus accumbens (NAc) is a crucial region in the reward circuit and is related to anhedonia, the pivotal symptom of major depression disorder (MDD). Deep brain stimulation (DBS) of NAc has been identified as an effective treatment for severe refractory major depression; however, the underlying mechanism of NAc-DBS in MDD treatment remains elusive. Using the chronic unpredictable mild stress (CUMS) mouse model, we found NAc-DBS rescued depression-like behaviors, and reversed high gamma oscillation reduction and neurogenesis impairment in the dorsal dentate gyrus. Inactivation of parvalbumin (PV)-positive interneurons (PVI) in the dorsal DG led to depression-like behavior and decreased adult neurogenesis. Further investigation elucidated the VTA-DG GABAergic projection and CA1-NAc projection might jointly participate in NAc-DBS therapeutic mechanism. Disinhibition of the VTA-DG GABAergic projection had an antidepressant effect, and inhibition of the CA1-NAc projection reduced the antidepressant effect of DBS-NAc. Moreover, disinhibiting the VTA-DG GABAergic projection or activating the CA1-NAc projection could increase PVI activity in the dorsal DG. These results showed PVI in the dorsal DG as an essential target in depression and NAc-DBS antidepressant mechanisms.