bluuebunny/crossref_metadata_2025 huggingface dataset:
CALBINDIN-POSITIVE PYRAMIDAL NEURONS IN HIPPOCAMPAL CA1 MEDIATE EARLY-LIFE STRESS-INDUCED COGNITIVE IMPAIRMENT IN MICE
Authors: Li *Xuexin , Sun Yaxin , Su Yunai , Li Jitao , Si Tianmei
Published: February 2025

Background

Early-life stress (ELS) can cause persistent and irreversible damage to the development, plasticity, and cognitive function of the hippocampus, leading to depression and other mental illnesses. However, the mechanism of negative effects induced by ELS remained unclear.

Aims & Objectives

Calbindin (CB) is one of the molecular markers of the superficial pyramidal neurons (PNs) of the hippocampal CA1 area. Previous research found that calbindin-positive (CB+) PNs and calbindin-negative (CB-) PNs in hippocampal dorsal CA1 (dCA1) region may play distinct roles in the regulation of cognition. Thus, the aim of this study was to explore the mechanism of different types of PNs in mediating ELS- induced cognitive deficits, and to provide new insights for the prevention and treatment of the stress- related mental disorders such as depression.

Method

We adopted the early-life stress model of the "limited bedding and nesting materials", and explored its impact on cognitive functions as well as neural activity and morphological plasticity of CB+ PNs and CB- PNs in dCA1 using behavioral, morphological and molecular biology techniques. Then, we selectively inhibited or activated CB+ PNs or CB- PNs in dCA1 with combination of transgenic mice and chemogenetic techniques to investigate the roles of different types of PNs in mediating cognitive impairment induced by ELS.

Results

ELS significantly impaired the cognitive performance in spatial object recognition (SOR) task, as well as the c-Fos expression of PNs in dCA1 after SOR task, with the activation of CB+ PNs outweighing CB- PNs. The dendritic complexity of CB+ PNs was damaged by ELS, but remained unaffected for CB- PNs. Specific inhibition of CB+ PNs in dCA1 mimicked the negative effect of ELS on cognitive functions, while inhibition of CB- PNs did not. Specific activation of CB+ PNs in dCA1 successfully reversed the cognitive impairment caused by ELS, whereas activation of CB- PNs failed to do so.

Discussion & Conclusion

Our findings indicate that calbindin-positive pyramidal neurons in dorsal hippocampal CA1 mediate the mechanism of cognitive impairment induced by early-life stress. Thus, calbindin-positive neurons in hippocampal CA1 may present new target for the prevention and treatment for cognitive dysfunction in stress-related mental illnesses such as depression.
ADOLESCENT BINGE DRINKING INDUCES BEHAVIORAL ABNORMALITIES IN ADULTHOOD CAUSED BY MYELIN ABNORMALITIES
Authors: Kunisawa *Kazuo , Sugawara Yumika , Yoshidomi Kohei , Kon Yuki , Saito Kuniaki , Nabeshima Toshitaka , Mouri Akihiro
Published: February 2025

Background

Adolescent binge drinking represents a major public health challenge and lead to persistent psychiatric disorders. However, the underlying pathogenic mechanisms remain poorly understood. Myelin abnormalities were observed in human subjects with alcohol abuse.

Aims & Objectives

In the present study, we investigated whether myelin abnormalities are involved in behavioral abnormalities induced by adolescent binge ethanol treatment (ABET).

Method

To produce ABET, C57BL/6J mouse was given EtOH (3.0g/kg, i.g. 25% ethanol w/v) once a day during adolescence (P28-46) in an intermittent fashion.

Results

ABET persistently developed behavioral abnormalities such as anxiety-like behaviors in the marble burying test and the novelty suppressed feeding test, impaired memory function in the novel object recognition test, and impairment of social interaction. ABET decreased myelin-related protein and mature oligodendrocytes through impaired oligodendrogenesis in the prefrontal cortex and hippocampus. Inhibiting adolescent myelination by deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursor cells increased susceptibility to behavioral abnormalities induced by a subthreshold ABET, while promoting oligodendrogenesis and myelination via clemastine treatment rescues the ABET-induced behavioral abnormalities.

Discussion & Conclusion

These findings suggest that myelin abnormalities caused by ABET may be involved in the behavioral abnormalities in adulthood.
THE INFLUENCE OF DISSOCIATIVE RESPONSE ON CORTISOL LEVEL FOLLOWING CHILDHOOD AND LATER TRAUMA: A PATH ANALYSISTHE INFLUENCE OF DISSOCIATIVE RESPONSE ON CORTISOL LEVEL FOLLOWING CHILDHOOD AND LATER TRAUMA: A PATH ANALYSIS
Authors: Yang *Chaeyeon , Kwon Aeran , Jung Bori , Lee Seung-Hwan
Published: February 2025

Background

Exposure to trauma during childhood can increase a risk of later traumatic experiences and dissociative responses. Furthermore, several studies found that dissociation is related with cortisol levels.

Aims & Objectives

In this study, we examined the impact of dissociative responses to traumatic experiences on cortisol levels in the general population with traumatic experiences.

Method

A total of one hundred seventy-five participants were recruited and had their morning cortisol levels measured. Clinical assessments were performed, including the Childhood Trauma Questionnaire (CTQ), Life Events Checklist (LEC), Peritraumatic Dissociative Experiences Questionnaire (PDEQ). Partial correlation and path analyses were conducted controlling age, sex, years of education, and BMI.

Results

Partial correlation showed that childhood trauma was positively correlated with later traumatic events and dissociation. In addition, multiple path analysis indicated that the direct effects of childhood trauma on later trauma, childhood trauma on dissociation, later trauma on dissociation, and dissociation on cortisol level were significant. However, partial mediation model which added a direct path from childhood trauma to cortisol level was insignificant.

Discussion & Conclusion

These findings suggest that dissociation is a critical factor related to altered cortisol levels in people who experienced childhood and later traumatic events.
(2R,6R)-HYDROXYNORKETAMINE TARGETING THE BASOLATERAL AMYGDALA REGULATES FEAR MEMORY
Authors: Xu *Yuanyuan , Li Zhenlong , Lee Chau-Shoun , Peng Hsien-Yu , Lin Tzer-Bin , Hsieh Ming-Chun , Lai Cheng-Yuan , Chou Dylan
Published: February 2025

Background

(2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, is a promising next-generation antidepressant known for its rapid and long-lasting effects. Recent studies have explored its impact on memory, yet its influence on fear memory extinction remains uncharted.

Objective

We investigated (2R,6R)-HNK's effects on synaptic transmission and plasticity in the basolateral amygdala (BLA) and its role in auditory fear memory extinction.

Method

Adult male C57BL/6J mice were utilized for extracellular electrophysiological recordings and fear conditioning tests.

Result

(2R,6R)-HNK at 30 mg/kg increased cfos-positive cell count in the BLA and dose-dependently enhanced long-term potentiation (LTP) induction and maintenance. Moreover, (2R,6R)-HNK improved BLA synaptic transmission. Both local and systemic administration of (2R,6R)-HNK reduced recent and remote fear memory retrieval and inhibited spontaneous remote fear memory recovery.

Conclusion

(2R,6R)-HNK could be a potential treatment for posttraumatic stress disorder (PTSD) patients by regulating BLA synaptic function and fear memory modulation.
BEHAVIORAL ANALYSIS OF MOTIVATED-BEHAVIOR-DEFICITS IN PACLITAXEL-INDUCED NEUROPATHY MODEL MICE
Authors: Otsuki *Tomofumi , Junqueira Joao Pedro , Matsumoto Jumpei , Setogawa Tsuyoshi , Uta Daisuke , Nishimaru Hiroshi
Published: February 2025

Numerous clinical studies have shown that chronic pain patients very often suffer from affective disorders, such as depression accompanied by decreased motivation. It has been proposed that they share a common neuronal mechanism since it has been reported that the rate of psychiatric disorders in chronic pain patients is approximately two to three times higher than in non-patients (McWilliams et al. Pain, 106:127-133, 2003). Central sensitization is one of the prominent hypotheses for the neuropathology of chronic pain of which pain information is abnormally amplified in the brain due to altered function of sensory-related regions which also affects emotion-related regions as well. Several preclinical studies have shown that deficit in motivated-behavior in animal persistent-pain models. However, the underlying neuronal mechanism remains largely unraveled. In rodents, locomotion is known to be essential for seeking and obtaining reward while licking behavior have been indicated as a crucial behavioral signal for expectation of reward. In this study, we examined these behavioral parameters in a paclitaxel-induced peripheral neuropathy (PIPN) mouse model. These mice exhibit mechanical allodynia and depression-like behavior for 2-3 weeks after intraperitoneal injection of paclitaxel (Toma et al. Neuropharmacology 17:305–315, 2017). We examined their changes of behavioral parameters during operant conditioning task that enabled us to quantitatively analyze licking and locomotion. Mice were water-restricted, placed on a polystyrene disc with their head fixed and trained to perform a locomotor operant task that required them to start running spontaneously to trigger the following trial. After running for 1 second, a drop of water was delivered from the spout as a reward, followed by a 2 second quiescence period. Trained mice achieved success rate over 80 % after 8-10 sessions were randomly assigned to PIPN group (n = 6) or control group (n = 7) and examined task performance for 4 weeks. PIPN mice showed altered performance during the second week after injection. During this period, the mean success rate in PIPN group significantly dropped (as low as 66%) but not in control group. In unsuccessful trials, mice typically stopped prematurely before reaching the goal. Moreover, the frequency of anticipatory licking significantly decreased in PIPN mouse. However, total running distance during the task remained unchanged. These results indicate that PIPN mice show deficits in motivational behavioral parameters during the period which they go through persistent pain. The behavioral paradigm in this study could be a useful to study mouse pain models to elucidate the neuronal mechanism of deficits in motivational behavior. This work was supported by JST SPRING, Grant Number, JPMJSP2145 (TO), Tamura Science &Technology Foundation (HN), Takeda Science Foundation (HN), KAKENHI No, 23H04673 (HN).
INHIBITION OF HISTAMINE METABOLIZING ENZYME IN THE BRAIN REDUCES CATAPLEXY IN NARCOLEPSY MODEL MICE
Authors: Yoshikawa *Takeo , Girgin Birkan , Agu Anne Bernadette , Nakamura Tadaho , Yanai Kazuhiko , Mochizuki Takatoshi , Nagasawa Shota , Iwabuchi Yoshiharu , Naganuma Fumito
Published: February 2025

Histamine plays a role as neurotransmitter to exert wake-promoting effects in the brain. Decreased histamine concentration in cerebrospinal fluid of narcolepsy patients suggested that the dysfunction of histamine system in the patients was involved in narcolepsy pathophysiology, suggesting that drugs increasing brain histamine level ameliorated narcolepsy symptoms. Thus, we hypothesized that inhibition of histamine metabolizing enzyme, histamine N-methyltransferase (HNMT), could increase brain histamine concentration and alleviate cataplexy by activating histamine system. First, we examined the pharmacological actions of metoprine, a HNMT inhibitor, on wild type mice. Metoprine significantly increased histamine contents in the brain but not lung, skin and stomach, however, metoprine did not change the concentrations of other monoamines such as dopamine, serotonin and norepinephrine. EEG (electroencephalogram) recording and pharmacological assays revealed that elevated histamine extended wakefulness of wild type mice by the activation of histamine H1 receptors. Next, we investigated the therapeutic potential of metoprine on narcolepsy model mice. Administration of metoprine significantly reduced the number and duration of cataplexy in the model mice. Although we confirmed the therapeutic effect of pitolisant, which increases brain histamine release and is approved in USA and EU for the narcolepsy treatment, the efficacy of metoprine was better than that of pitolisant, emphasizing the sufficient therapeutic potential of HNMT inhibitors against narcolepsy. Unfortunately, there was no HNMT inhibitors with high permeability of blood-brain barrier and high specificity. Thus, we performed compound screening to obtain novel HNMT inhibitors available for narcolepsy treatment. After the structural optimization of candidate compounds, we got several compounds with low IC50 values to HNMT enzymatic activity.In the present study, we demonstrated that elevated brain histamine by HNMT inhibition robustly induced wakefulness and improved the symptoms of narcolepsy model mice. Further studies are essential to obtain therapeutic compounds for the treatment of human narcolepsy.
POGZ MUTANT MOUSE MODEL OF AUTISM SPECTRUM DISORDER SHOWS ABNORMAL NEURAL ACTIVITY IN THE ANTERIOR CINGULATE CORTEX DURING SOCIAL BEHAVIOR
Authors: Kitagawa *Kohei , Takemoto Tomoya , Seiriki Kaoru , Kasai Atsushi , Hashimoto Hitoshi , Nakazawa Takanobu
Published: February 2025

Background

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication. Despite its high prevalence, neural pathogenesis of ASD is largely unknown. The anterior cingulate cortex (ACC) is critically involved in various cognitive processes and has been reported to be associated with social communication. Recent studies suggest that impaired ACC function may be associated with social impairment in ASD, however the detailed underlying neural mechanisms are unclear. We previously demonstrated that a mouse model carrying an ASD patient-derived mutation in POGZ, one of the genes most significantly associated with ASD (POGZ mutant mice), showed ASD-like behavioral deficits, including impaired social communication.

Aims & Objectives

Here, to understand the neural mechanisms behind the impaired social communication in POGZ mutant mice, we measured the neural activity in the ACC by fiber photometry in freely moving mice.

Methods

Fiber photometry was employed to examine neural activities in freely moving mice participating in social interaction tests. Wild-type (WT) and POGZ mutant mice were injected with AAV-CamKIIα-GCaMP6f in the ACC, followed by the implantation of optic cannula. Ca2+ signals were recorded during 5-minute social interaction tests, at a minimum of 3 weeks post-injection.

Results

We initially confirmed that POGZ mutant mice exhibited reduced social interaction time compared to their WT littermates, consistent with our previous report. Through fiber photometry recordings, we observed an elevation in Ca2+ signals of ACC pyramidal neurons upon the introduction of intruder mice in both WT and POGZ mutant mice. Remarkably, the average Ca2+ signals of ACC pyramidal neurons in the presence of intruder mice were significantly higher in POGZ mutant mice. In contrast, the neural activity in the ACC pyramidal neurons in POGZ mutant mice displayed reduced responsiveness to the initiation of each social investigation in comparison to that in WT mice. These results suggest that the ACC neural activity governing social behavior is impaired in POGZ mutant mice.

Discussion & Conclusion

These findings suggest a neurobiological link between the dysregulation of neural activity in ACC pyramidal neurons and social impairment in POGZ mutant mice, thereby shedding light on potential avenues for the development of novel therapeutics for ASD.
MICROBIAL METABOLITES REGULATE SOCIAL NOVELTY VIA CAMKII NEURONS IN THE BNST
Authors: Liou Chia-Wei , Cheng Sin-Jhong , Yao Tzu-Hsuan , Lai Tzu-Ting , Tsai Yu-Hsuan , Wu *Wei-Li
Published: February 2025

Background

Social novelty is a cognitive process that is essential for animals to interact strategically with conspecifics based on their prior experiences. The commensal microbiome in the gut modulates social behavior through various routes, including microbe-derived metabolite signaling.

Aims & Objectives

Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior.

Method

We interrogate the functional role of SCFAs in the brain and social behavior via intracerebroventricular infusion of SCFAs in freely moving mice. Electrophysiology, chemogenetic manipulation, and Cre- dependent cell ablation were employed to unravel the neural circuit by which SCFAs alter social behavior.

Results

Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We observed that infusion of SCFAs into the lateral ventricle disrupted social novelty in microbiome-depleted mice without affecting brain inflammatory responses. The deficit in social novelty can be recapitulated by activating calcium/calmodulin-dependent protein kinase II (CaMKII)-labeled neurons in the bed nucleus of the stria terminalis (BNST). Conversely, chemogenetic silencing of the CaMKII-labeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAs-induced deficit in social novelty.

Discussion & Conclusion

Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST.

References

Liou CW, Cheng SJ, Yao TH, Lai TT, Tsai YH, Chien CW, Kuo YL, Chou SH, Hsu CC, Wu WL. Microbial metabolites regulate social novelty via CaMKII neurons in the BNST. Brain Behav Immun. 2023 Oct;113:104-123. doi: 10.1016/j.bbi.2023.06.029. Epub 2023 Jun 29. PMID: 37393058.
IMPORTANCE OF β-PHENYLETHYLAMINE (PEA) NEURONAL SYSTEM, EQUIVALENT TO D-NEURON SYSTEM AND TAAR1 LIGAND NEURON SYSTEM
Authors: Ikemoto *Keiko
Published: February 2025

Background

β-phenylethylamine (PEA) is a trace amine, recently regarded as a neurotransmitter, rather than a neuromodulator, of which chemical structure is similar to amphetamine, mescaline or catecholamines. The PEA neuron may have aromatic L-amino acid decarboxylase (AADC) as a synthesizing enzyme, TAAR1 as a receptor, and MAOB as a degrading enzyme [1, 2, 3].

Aims & Objectives

PEA affects on animal behaviours and human mental states. TAAR1 medicinal chemistry is prospective psychopharmacological field. The present study highlights PEA neuronal system.

Methods

Brains of mice, rats, monkeys and MAOA KO mice, and human post-mortem brains were used. AADC immunohistochemistry and MAO enzyme histochemistry was applied.

Results

Distribution of mouse D-neurons was overall overlapped with MAOB-positive neurons shown by applying MAO enzyme histochemistry to MAOA KO mice. In humans, D-neuron system was developped in the thalamus, striatum and nucleus accumbens, compared to rodents and monkeys. D-neuron system had distinct species differences.

Discussion & Conclusion

There are accumulating evidences showing that PEA neuronal system is equivalent to D-neuron system and TAAR1 ligand neuron system. Understanding of this neuronal system would serve to develop treatment of neuropsychiatric disaeses and TAAR1 medicinal chemistry.

References

1Grimsby J et al. Nat Genet 17: 206-210, 1997

2Ikemoto K et al. Brain Res 771: 121-132, 1997

3Ikemoto K et al. In: Trace Amine and Neurological Disorders, Eds Tahira Farooqui &Akhlaq A Farooqui, pp.295-307, 2016
NEURONAL CIRCUITS AND NEURONAL MEMBRANE PROPERTIES INVOLVED IN EMPATHY
Authors: Yoshida *Takayuki , Youdai Umakoshi , Hashimoto Kouichi
Published: February 2025

Empathy is a cognitive and emotional response that occurs in individuals who observe the experiences of others. In this study, we aimed to understand the neural circuit mechanisms involved in empathy by using the observational fear learning (OFL) test, immunohistochemical (IHC) and patch-clamp (PC) analyses in mice. We labeled pyramidal cells in the dorsal medial prefrontal cortex (dmPFC) that project to the basolateral lateral amygdala (BLA) or periaqueductal gray (PAG) and control fear and its associated behaviors, respectively, and analyzed the neuronal activity induced by OFL using c-fos expression as an indicator for IHC analysis. PAG projection neurons were both activated by about 15%. PC analysis of the membrane potential properties of dmPFC pyramidal cells under normal conditions revealed that BLA- or PAG-projecting pyramidal cells fired action potentials more frequently than did non-projecting pyramidal cells. These results suggest that BLA- or PAG-projected dmPFC pyramidal cells express empathy by suppressing their excitability.
DOES COCAINE-INDUCED AGGRAVATION OF DEPRESSION ALTER MATE ATTRACTIVENESS IN MALES?
Authors: Ohnishi *Yoshinori N , Kawahara Yukie , Ohnishi Yoko , Nishi Akinori
Published: February 2025

Social defeat stress is a recognized method to induce depressive-like behaviors in mice. Our study found that when mice subjected to social defeat stress were later administered with cocaine, their depressive state significantly worsened. Notably, the typical anti-depressive effects gained from overexpressing DFosB in the nucleus accumbens (NAc), a region known for mediating anti-depressive states, failed to counteract the exacerbating effects of cocaine. Interestingly, a pre-treatment involving electrical shocks to the brain triggered the induction of endogenous DFosB, generating an anti-depressive effect.

Nevertheless, even in this mitigated state, subsequent cocaine administration reinstated the depressive behaviors. To robustly verify the intensification of the depressive state, behavioral paradigms like the elevated plus maze and forced swim test were conducted both before and after cocaine treatment. A notable deterioration in performance was observed specifically in the forced swim test post-cocaine administration. Given our understanding that male attractiveness in mice is influenced by physical appearance and perceived confidence, we postulated how this intensified depressive state might affect a male's attractiveness. Observations revealed that during the depressive state induced by social defeat, dopaminergic neurons in the ventral tegmental area (VTA) exhibit hyperactivity. Building on this, we employed a retrograde AAV DIO Gi and Gq injection into the NAc of TH-cre mice. The objective is to delineate the impact of dopaminergic neuron activity on both male attractiveness and the depressive state under the combined influence of social defeat and cocaine. In conclusion, this study illuminates the intricate relationship between cocaine, social defeat-induced depression, and male attractiveness, providing crucial insights into the underlying neurobiological mechanisms and potential therapeutic interventions.
N,N-DIMETHYLTRYPTAMINE, A NATURAL HALLUCINOGEN, AMELIORATES ALZHEIMER’ S DISEASE BY RESTORING NEURONAL SIGMA-1 RECEPTOR- MEDIATED ENDOPLASMIC RETICULUM-MITOCHONDRIA CROSSTALK
Authors: Cheng Dan , Zhang *Zhang-Jin
Published: February 2025

Background

Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated signaling between the endoplasmic reticulum (ER) and mitochondria plays an essential role in neuronal cytopathology of Alzheimer’ s disease (AD). The natural hallucinogen N,N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti- AD potential by protecting neuronal ER-mitochondrial interplay.

Aim and Objectives

The purpose of this study was to systematically investigate the anti-AD effects of DMT and the association with its restoration of neuronal ER-mitochondria signaling.

Methods

Effects of chronic DMT (2 mg/kg) for 3 weeks on cognitive impairment and Aβ deposits were examined in 3× TG-AD transgenic mouse model of AD. The effects of DMT on the expression of Sig-1r and mitochondria-associated membranes (MAM)-associated proteins, physical contact, and calcium dynamic between ER and mitochondria were detected in in vitro and in vivo paradigms, with the utilization of Sig-1r knockdown mice and the Sig-1r antagonist BD1063.

Results

Chronic DMT markedly alleviated cognitive impairment in water maze of 3× TG-AD transgenic mice. In parallel, it largely diminished Aβ deposits in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of the transgenic and knockdown mice and in cultured hippocampal neurons co-treated with BD1063. DMT prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. The hallucinogen also reinstated the expression of multiple mitochondria-associated membrane (MAM)-associated proteins in 3× TG-AD mice.

Discussion and Conclusions

These results suggest that the anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the Sig-1r activation. DMT may serve as a novel preventive and therapeutic agent against AD.
REGULATION OF THE TRANSITION BETWEEN MEMORY RECALL AND NON- RECALL BY HISTAMINE NEURON ACTIVITY
Authors: Takamura *Yuki , Morishita Yoshikazu , Nishimura Kyoka , Hitora(Imamura) Natsuko , Minami Masabumi , Nomura Hiroshi
Published: February 2025

Background

The spontaneous recollection of forgotten memories remains a puzzling aspect of cognitive function, with uncertain mechanistic underpinnings. Brain histamine is produced in the tuberomammillary nucleus (TMN) and is involved in various functions, including learning and memory. In our previous work, we demonstrated that upregulating histamine release by administrating histamine H3 receptor inverse agonists promotes the recall of forgotten memories.

Aims & Objectives

The purpose of this study is to examine whether and how histamine neuronal activity regulates the transition between recall and non-recall.

Method

To probe the dynamics of histaminergic neuronal activity during associative tone-reward learning, we employed fiber photometry. Specifically, a genetically encoded fluorescent calcium sensor GCaMP6s was expressed in histamine neurons within the mouse TMN, and its fluorescence was monitored through implanted optical fibers. We assessed the impact of histamine neuronal activity on associative memory recall by optogenetically inhibiting these neurons. We expressed a light-sensitive chloride ion pump, NpHR, in TMN histamine neurons and utilized green light illumination to modulate their activity.

Results

After several days of tone-reward conditioning, the mice exhibited predictive licking responses following tone presentations in some trials (recall trials), whereas such responses were absent in other trials (non-recall trials). We compared the histamine neuronal activity between the recall and non-recall and found that the histaminergic neuronal activity preceding the conditioned stimulus (CS) correlated with memory recall performance. To test whether elevated histamine neuron activity preceding the CS fosters associative memory recall, we employed closed-loop CS presentation contingent on histaminergic neuronal activity. The recall performance was enhanced when the CS was presented during elevated histaminergic neuronal activity as opposed to constant activity levels. Furthermore, optogenetic inhibition of histaminergic neurons prior to the CS attenuated associative memory recall.

Discussion & Conclusion

These results suggest that the activity of histamine neurons preceding the presentation of a memory recall cue is a key regulator in determining the accessibility of stored memories.
EXPLORE THE ASSOCIATION OF SWEET PREFERENCE WITH THE TREATMENT RESPONSE TO NALTREXONE IN PATIENTS WITH ALCOHOL USE DISORDER
Authors: Chang *Min Chiao , Meng Shih-Chun , Huang Ming-Chyi
Published: February 2025

Background

Alcohol use disorder (AUD) is a prevalent psychiatric issue worldwide, contributing to the global burden of morbidity and mortality. While pharmacological interventions have been developed to manage AUD, the efficacy of Naltrexone, the first-line treatment, varies among individuals. Identifying phenotypes associated with naltrexone response is essential for optimizing treatment plans. Naltrexone functions by attenuating the reward signals from the endogenous opioid system, which is also linked to the hedonic response to sweet tastes. Naltrexone has been observed to have a better response in patients with a preference for sweet tastes in Western populations. However, it remains unknown whether sweet preference serves as a predictive phenotype for therapeutic response in Taiwan.

Aim and Objective

The study aimed to examine the association between sweet preference and naltrexone response in Taiwanese patients with AUD.

Method

A total of 56 patients diagnosed with AUD as per DSM-5 criteria participated in this study. They underwent a sweet preference test, rating their pleasurableness of various concentrations of sucrose. Following the preference test, they underwent a 12-week treatment, with evaluations at the end of weeks 2, 4, 8, and 12 to assess drinking outcomes. The drinking outcomes were measured by days to first drink after treatment initiation, maximum daily drinks, average daily drinks, and craving severity measured by Visual Analogue Scale (VAS). The generalized estimating equation and the Mann-Whitney test were applied to investigate the difference in drinking outcomes between sweet-liking and sweet- disliking groups.

Result

Participants were dichotomously classified into the sweet-liking (SL) group (n =28) and the sweet- disliking (SDL) group (n = 28) by comparing their pleasurableness ratings at 0.2M to the median pleasurableness ratings of all participants at 0.2M. We observed no significant differences in demographics between the SL and SDL groups. The time to their first drink was significantly longer in the SL group compared to the SDL group (57.8 days vs. 42 days, p = 0.03). Participants in the SL group also reported a lower daily drinking amount, both maximal (1.1 drinks vs. 5.4 drinks, p = 0.02) and average (1.5 drinks vs. 5.8 drinks, p = 0.01), after four weeks of treatment. By the end of the 12-week period, the SL group also exhibited lower VAS scores compared to the SDL group.

Discussion and Conclusion

Ours is the first study in Taiwan to indicate that patients with AUD with a preference for sweet taste responded better to naltrexone treatment in terms of drinking outcomes, specifically, a longer period of abstinence, reduced craving, and an earlier reduction in drinking amount. Future studies should focus on expanding the understanding of precision medicine in AUD treatment.
DISRUPTION OF IMPULSIVITY BEHAVIORS IN CANNABIS USERS IN ADOLESCENTS AND YOUNG ADULTS: A META-ANALYSIS OF FUNCTIONAL NEUROIMAGING STUDIES
Authors: Zhang *Yuxin , Liu Xiao-Xing , Li Ming-Zhe , Li Peng , Bao Yan-Ping , Lu Lin
Published: February 2025

Background

Cannabis is a widely used controlled psychoactive substance. Increased dopamine excitation transmission reduced the capacity of controlling impulsivity behaviors which contributed to their growing desire to drugs, especially teenager and young adults. In cannabis users, the effect of cannabis on impulsivity control behaviors mainly reflected in impulsivity control, inhibitory control and delayed reward discounting, however no unified conclusion has made.

Aims & Objectives

We sought to perform a meta-analysis to clarify the effect of cannabis use on impulsivity control behaviors and dynamic changes of brain regions during impulsivity control process of cannabis users in teenage and early adulthood.

Method

A systematic search of the PubMed, Embase and Web of Science was performed to identify fMRI studies that were published from the inception up to August 20th, 2023, which reported the brain activation during impulsivity control process of cannabis users in teenage and early adulthood. Backward citation tracking was also performed. Seed-Based d Mapping (SDM) was applied to combine the statistical maps, coordinates and t-values of the peaks in each study. We concerned the sources of heterogeneity by subgroups and meta-regression.

Results

28 studies with 1381 individuals were included in the analysis. Compared to healthy controls, cannabis users in adolescents and early adulthood showed weakened impulsivity control capacity. Besides, cannabis users during abstinence period showed increased responses in bilateral anterior thalamic projections and cingulate cortex during impulsivity control process compared with healthy controls. Further, cannabis users with early onset age showed worse inhibition capacity in cingulate cortex and medial prefrontal cortex. Increased activation in cingulate cortex and better inhibition in striatum were correlated with better performance in impulsivity control tasks.

Discussion & Conclusion

This review and meta-analysis indicates attenuation in impulsivity control behaviors in teenage and early adulthood cannabis users. During impulsivity control process, increased activation in cingulate cortex was shown in adolescents and early adulthood cannabis users. Earlier cannabis intake could cause dysregulation of cingulate cortex and medial prefrontal cortex in impulsivity control process. Protective measures should be taken to reduce the possibility of adolescents' exposure to cannabis and attenuate the damage of cannabis to the brain.
GENOMIC AND IMMUNOLOGICAL BIOMARKERS FOR PREDICTING TREATMENT OUTCOME IN DEPRESSION
Authors: Ising *Marcus , Belcredi Petra , Lucae Susanne , Tontsch Alina , Namendorf Christian , Uhr Manfred , Holsboer Florian , Rex-Haffner Monika , Simulionyte Egle , Hebib Sandi , Gruber Oliver , Behler Nora , Nenov-Matt Tabea , Schüle Cornelius , Manook André , Heckel Barbara , Baghai Thomas , Rupprecht Rainer
Published: February 2025

The aim of this project is the validation of genomic and non-genomic biomarkers for predicting antidepressant treatment outcome to identify biologically more homogenous subgroups of patients that might benefit from specific treatments targeting the identified biomarker system. Based on previous findings, we focused on the stress regulation gene FKBP5 for the selection of the genomic biomarkers and on a set of 41 cytokines/chemokines for defining immunological biomarkers. 307 inpatients hospitalized for treating a major depressive episode were included, who participated in the MARS/OptiMD study. MARS/OptiMD is an open-label multicentric treatment study conducted at four clinical centers in Germany. Biomarkers were extracted from DNA, RNA, and serum samples collected after study inclusion. Antidepressant treatment outcome was evaluated weekly by trained personal with the 21-items Hamilton Depression Rating scale (HAMD-21). Primary endpoint in this analysis was response after six weeks of treatment defined as a 50% HAMD-21 reduction compared with baseline.

Replicating our previous findings with suggestive evidence, we observed that reduced FKBP5 expression was associated with response with approaching significance, and this trend was moderated by the FKBP5 genotype (rs1360780). Using Illumina EPIC Methylation BeadChips, we identified 67 DNA methylation markers located within the boundaries of the FKBP5 gene. A principal component analysis revealed five vectors with two (vector 1 and vector 2) showing a robust positive association between higher methylation levels and antidepressant treatment response. Again, these effects were moderated by the rs1360780 genotype. Among 41 cytokines/chemokines, six markers showed an association with treatment response with the strongest effect observed for interleukin 13. For interleukin 3, a trend was found towards an association with treatment response that was moderated by the individual CRP level as marker of the inflammation status. A combined analysis of both types of biomarkers, genomic and immunological, suggests that the observed effects on treatment outcome are independently from each other. Our results confirm and extend previous findings on the prominent role of genomic FKBP5 biomarkers, and partly also of cytokines/chemokine biomarkers, for predicting antidepressant treatment outcome in depression. Importantly, these effects are moderated by person factors like the FKBP5 genotype and the individual inflammation status, pointing to a suitability of these markers in identifying subgroups of patients that might benefit from personalized treatments targeting the associated biomarker systems.
EFFECT MODIFICATION OF TUMOR NECROSIS FACTOR-α ON THE KYNURENINE AND SEROTONIN PATHWAYS IN MAJOR DEPRESSIVE DISORDER ON TYPE 2 DIABETES MELLITUS
Authors: Okamoto *Naomichi , Hoshikawa Takashi , Honma Yuichi , Chibaatar Enkhmurun , Ikenouchi Atsuko , Harada Masaru , Yoshimura Reiji
Published: February 2025

Background

Major depressive disorder (MDD) is strongly associated with type 2 diabetes mellitus (T2DM). The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to antidepressants than that without T2DM; however, the underlying mechanism remains unknown.

Aims & Objectives

We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD.

Method

We recruited 13 patients with comorbid MDD and T2DM and 40 patients with MDD. We measured interleukin- 6 and tumor necrosis factor-α (TNF-α) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two.

Results

TNF-α levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p = 0.044) and multivariate (adjusted p = 0.036) analyses. TNF-α showed a statistically significant effect modification (interaction) with quinolinic acid/tryptophan and serotonin in patients from both groups (β = 1.029, adjusted p <0.001; β = −1.444, adjusted p = 0.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited.

Discussion & Conclusion

MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM.
EFFICACY AND SAFETY OF ADJUNCTIVE LURASIDONE IN TREATMENT RESISTANT UNIPOLAR DEPRESSION : AN OPEN-LABEL SINGLE-ARM PILOT STUDY
Authors: Chiu *Nan-Ying , Chang Cheng-Ju
Published: February 2025

Background

Major depressive disorder (MDD) is a recurrent, chronic, and disabling disorder worldwide. Antidepressant treatment is an important evidence-based therapy. However, the response rate of antidepressant therapy is unsatisfied. Lots of evidence indicates atypical antipsychotic is an efficient choice for adjunctive therapy for patient with treatment resistant depression (TRD), but only aripiprazole, quetiapine and brexpiprazole are indicated. Lurasidone is a novel atypical antipsychotic as a serotonin-dopamine modulator. Its pharmacological mechanism may be beneficial for depressed mood with few notable adverse effects. The efficacy and safety of lurasidone adjunctive therapy in MDD is not yet well established.

Objectives

This clinical study aimed to explore efficacy and safety of lurasidone as adjunctive therapy for TRD patients.

Methods

This is an 8-week open-label single-arm study, enrolled TRD cases. Use lurasidone as adjunctive drug treated with antidepressant. We select Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression- severity (CGI-S), Clinical Global Impression- Improvement (CGI-I) as assessment tools. Evaluation were done at baseline, week 2, week 4, and week 8, included efficacy and safety.

Results

This is an interim report. Totally 17 patients enrolled, 7 males and 10 females, mean age was 39.0 (SD: 10.2) year-old, 58.8% were married, 35.3% were single, 47.1% employed, 41.2% were housewife, 58.8% were college/university graduated, 23.5% had suicide attempt history, mean number of previous MDE was 2.7 (SD: 1.9), mean duration of current MDE was 18.4 (SD: 4.3) weeks. Preliminary results indicated a trend of reduction of MADRS, and CGI (MADRS: P=0.001; CGI-S: P=0.002; CGI-I: P=0.004). The score of MADRS reduced from 32.6 (SD: 3.0) to 23.0 (SD: 2.62). The response rate was 52.9%, but the remission rate was 0%. Mean maximal dose of lurasidone was 35.3 (SD: 8.8) mg/day. Three mild adverse events were observed: sedation, nausea, weight gain.

Discussion & Conclusion

This pilot study found in a sample of TRD patients, suggest that lurasidone may be an effective and safe adjunctive drug. Our 8-week study found a response rate of 52.9%. The observed effect size on reducing depressive symptoms is substantial and clinically relevant. The findings should be interpreted with caution, as this is a single-arm small sample size study. Further double- blinded, randomized, placebo-controlled study is needed.

References

Trisha S, Robert S, Josephine C, et al. Lurasidone for the treatment of Major depressive disorder with mixed features: A Randomized, Double-Blind, Placebo-Controlled Study. Am J Psychiatry 2016; 173:400- 407.
TRANSLATIONAL ANIMAL MODELS OF ANTIDEPRESSANT EFFECTS, LONGITUDINAL BIOMARKER MONITORING IN RESPONDER/ NON RESPONDER MALE AND FEMALE MICE
Authors: Gorgievski *Victor , Ibrahim El Cherif , Le Marois Marguerite , Belzeaux Raoul , Tzavara Eleni
Published: February 2025

Background

Predictive biomarkers of antidepressant (AD) response, as well as ADs with novel mechanisms of action are an unmet medical need. Translational models that encompass both sexes, multiple ADs, and longitudinal monitoring are urgently needed to identify biomarkers that could inform new AD mechanisms and allow to test pharmacological hypotheses. Here we present two such models in male (M) and female (F) mice.

Aim and Objectives

We have previously shown that the transcription factor Elk1 is a mediator of the stress response in M mice. We expand these findings in F and test Elk1 expression as a novel biomarker differentiating ad hoc responders from non responders in both sexes.

Methods

We use M and F C57Bl6 mice in the unpredictable chronic mild stress (UCMS; n=107M, 113F) and the vicarious social defeat (vSD; n=60M, 60F) to longitudinally assess stress and fluoxetine (FL) or desipramine (DM) effects. We determine responders (R) and non-responders (NR) with principal component analysis across multiple behavioral tests. We perform transcriptomics in whole blood (sampled longitudinally) and RT-qPCR to validate candidate blood biomarkers (including Elk1) translated from previous and current (ANTaRES; ERANET Neuron) clinical trials.

Results

UCMS and vSD precipitate a depressive-like phenotype in both sexes with different trajectories in M and F (interaction p=0.016 UCMS; p=0.007 vSD). In R (which account for approximately 30% of AD treated M and F mice) AD treatment overall reverses this phenotype with effects varying across behavioral test, sex and drug. RT-qPCR confirms Elk1 as a blood biomarker for stress and AD also in females (main effect p=0.003).

Conclusions

We validate two mouse models of AD action in M and F mice. Longitudinal behavioral and molecular (biomarker) monitoring reveals sex-dependent differences in stress and AD effects over time. We confirm Elk1 as a novel target and putative blood biomarker in both sexes.
ROLES OF CANNABINOID TYPE 1 RECEPTORS IN THE MICE PREFRONTAL CORTEX FOR OBJECT LOCATION MEMORY
Authors: Tokutake *Tomohiro , Asano Takashi , Izuo Naotaka , Muramatsu Shin-Ichi , Nitta Atsumi
Published: February 2025

Background

The cannabinoid type 1 receptor (CB1R) is stimulated by delta 9-tetrahydrocannabinol (THC) is the main component of cannabis. CB1R is a seven transmembrane Gi/o protein-coupled receptor. CB1Rs are mainly expressed in the brain1,2. CB1R regulates the release of some neurotransmitters from neurons such as GABAergic neurons3.Therefore CB1R is involved in the cognitive function such as memory4. The prefrontal cortex (PFC) is the brain region related to cognitive function5. The PFC is reported to be important for spatial cognitive function5,6.

Aims and Objectives

The relationship between CB1Rs in the PFC and spatial cognitive function remains unclear. In this study, we attempted to investigate the role of CB1R in the PFC by using the object location memory test, which can measure spatial cognitive function.

Methods

In this study, we administered arachidonylcyclopropylamide (ACPA) (10 ng/mice), a CB1R agonist, into the PFC of C57BL/6J mice (9 weeks, male) with the guide cannula and performed object location test. In object location test, memory formation was divided into three phases; acquisition, consolidation, and retrieval. First, we administered ACPA in three points. Second, we administered ACPA in once at each phase.

Results

The three intra-PFC administration of ACPA impaired object location memory. Furthermore, the single intra- PFC administration of ACPA impaired the memory acquisition. However, the consolidation and retrieval were not impaired.

Discussion and Conclusion

In this study, it was indicated that CB1R in PFC is associated with the acquisition of object location memory. These results may be useful for the functional analysis of CB1R in the PFC.

References

1.Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991), Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. J Neurosci. 11:563-583. https://doi.org/10.1523/JNEUROSCI.11-02-00563.1991.

2.Grass M, Dragunow M, Faull RL (1997), Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 77:299-318. https://doi.org/10.1016/S0306-4522(96)00428-9.

3.Demuth DG, Molleman A (2006), Cannabinoid signalling. Life Sci. 78:549-563. https://doi.org/10.1016/j.lfs.2005.05.055.

4.Prini P, Zambeletti E, Manenti C, Gabaglio M, Parolaro D, Rubino T (2020) Neurobiological mechanisms underlying cannabis-induced memory impairment. Eur Neuropsychopharmacol. 36:181-190. https://doi.org/10.1016/j.euroneuro.2020.02.002.

5.Yan Z, Rein B (2020) Mechanisms of synaptic transmission dysregulation in the prefrontal. 27:445-465. https://doi.org/10.1038/s41380-021-01092-3.

6.Spellman T, Rigotti M, Ahmari SE, Fusi S, Gogos JA, Gordon JA (2015), Hippocampal-prefrontal input supports spatial encoding in working memory. Nature. 522:309-314. https://doi.org/10.1038/nature14445.
Mathematical modeling and analysis of emission and mitigation of methane from the integrated rice–livestock farming system
Authors: Verma Maitri , Kumar Verma Alok
Published: February 2025

Controlling the elevated levels of methane ($\textrm{CH}_{4}$) in the atmosphere is crucial to tackling the problem of climate change. Both rice paddies and livestock farming are substantial contributors to this elevated methane. The integrated rice–livestock farming system is an agricultural practice designed to optimize the use of agricultural waste, while concurrently boosting rice and livestock productivity. Achieving the dual objectives of food security and mitigating climate change demands formulation and implementation of strategies that are aimed at managing the methane emissions from the rice–livestock farming system. This study introduces a nonlinear mathematical model of the emission and mitigation of methane in the integrated rice–livestock farming system. Through qualitative analysis, the model’s dynamic behavior is thoroughly explored, identifying conditions for reduction and stabilization of atmospheric methane concentrations. Model parameters are estimated using secondary data on atmospheric methane concentration, rice yield and livestock population. A sensitivity analysis is presented to evaluate the influence of variations in crucial parameters on the system’s behavior. Numerical simulations are conducted to confirm the validity of the theoretical results.