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Background: The 3xTg-AD transgenic mouse model of Alzheimer's disease (AD) is an important tool to investigate the relationship between development of pathological amyloid-β (Aβ) and tau, neuroinflammation, and cognitive impairments. Traditional behavioral tasks assessing aspects of learning and memory, such as mazes requiring spatial navigation, unfortunately suffer from several shortcomings, including the stress of human handling and not probing species-typical behavior. The automated IntelliCage system was developed to circumvent such issues by testing mice in a social environment while measuring multiple aspects of cognition. Water consumption can serve as a primary motivator for task engagement. Once animals adapt to the cage and can access water, mice can be subjected to operant tasks. Each of the four corners of a cage contains doors to manipulate access to water, visual LED cues, and a valve allowing administration of an air puff. Previously, we detected significant impairments in 3xTg-AD mice in the IntelliCage, however a high failure rate and genotypical differences in water motivation were observed. Methods: Here, we implemented an IntelliCage paradigm where mice underwent progressively more difficult reaction time tasks to assess attention and impulsivity, behaviors mediated by the prefrontal cortex. Mice were placed in the IntelliCage at 11.5 months of age, which corresponds with the presence of widespread pathology. Results: As the difficulty of the reaction time tasks increased, 3xTg-AD mice exhibited lower percent Correct Responses than NonTg. When implementing varying pre-cue durations, where animals are required to wait between the initiation of the trial and the LED turning on (which then requires a nose-poke to access water), 3xTg-AD mice prematurely nose-poked on trials requiring a longer delay before a second nose poke would allow water access, demonstrating heightened impulsivity. The presence of soluble and insoluble fractions of cortical Aβ40 and 42, and phosphorylated tau epitopes threonine 181 and serine 396 confirmed the presence of neuropathological hallmarks in 3xTg-AD mice. Conclusion: Together, this study describes a novel protocol that overcomes motivational differences and detects attention and impulsivity deficits in 3xTg-AD mice utilizing the IntelliCage. [ABSTRACT FROM AUTHOR]

Chronic stress typically leads to deficits in fear extinction when tested soon after chronic stress ends. Given the importance of extinction in updating fear memories, the current study examined whether fear extinction was impaired in rats that were chronically stressed and then given a break from the end of chronic stress to the start of fear conditioning and extinction. Male rats were chronically stressed by restraint (6 h/d/21 d) and tested soon (termed immediate, STR-IMM), or 3 or 6 wk after a rest period from restraint (termed rest or "R," STR-R3, STR-R6). In Experiment 1, STR-R3 and STR-R6 discriminated between the cue and nonshock context better than STR-IMM or control. Interestingly, STR-IMM showed high freezing to the nonshock context. Consequently, Experiment 2 investigated whether STR-IMM generalized across contexts, which was not supported. Experiment 3 determined whether STR-IMM were susceptible to second-order conditioning to a novel context, but showed that the level of second-order conditioning was similar for all groups. These findings reveal that rats exposed to chronic stress and then given a rest period of 3 or 6 wk, express unique fear extinction profiles compared to control and STR-IMM. Specifically, STR-R demonstrated excellent cue and context discrimination during extinction, and perhaps showed a stress inoculation effect. For STR-IMM, the heightened freezing under these extensive acclimation parameters was not attributed to generalization nor to second-order fear conditioning to "safe" contexts and, instead, may reflect hypervigilance.

Objectives: To investigate the number of mental health‐related hospitalisations of adolescents (12–17 years) in South Australia by level of contact with the child protection system (0–11 years). Study design: Whole‐of‐population descriptive study; analysis of de‐identified linked administrative data from the Better Evidence Better Outcomes Linked Data (BEBOLD) platform. Setting, participants: Adolescents born in South Australia, 1991–1999; linked SA Department for Child Protection, Admitted Patient Care (SA Health), and South Australian Perinatal Statistics collection (SA Department for Health and Wellbeing) data. Main outcome measures: Proportion of adolescents (12–17 years) hospitalised with mental health‐related diagnoses; proportion of mental health‐related hospitalisations of adolescents, by level of child protection contact (0–11 years) (no contact, notification but not screened in, screened‐in notification but not investigated, investigation but not substantiated, substantiation, and out‐of‐home care). Results: Of 175 115 adolescents born during 1991–1999, 5646 (3.2%) had been hospitalised with mental health conditions, and 27 203 (15.5%) had histories of contact with child protection services. The proportion of adolescents admitted to hospital with mental health‐related diagnoses increased with the level of prior child protection contact, from 3366 of 147 912 adolescents with no contact (2.3%), to 398 of 6645 with notifications (6.0%), to 209 of 1191 who had been placed in out‐of‐home care (17.5%). Contact with child protection services was recorded for 2280 of 5646 adolescents admitted to hospital with mental health‐related diagnoses (40.4%); 4477 of 10 633 mental health‐related hospitalisations (44.9%) were of adolescents with histories of child protection services contact, including 1285 hospitalisations (12.1%) of adolescents for whom substantiated maltreatment (but not out‐of‐home care) was recorded, and 568 hospitalisations (5.3%) of adolescents who had been placed in out‐of‐home care. Conclusion: About 45% of mental health‐related hospitalisations of 12–17‐year‐old adolescents were of people who had had contact with child protection services by the age of 11 years, although only 15.5% of all adolescents had histories of child protection contact. The trauma associated with a history of child protection can have longer term sequelae, and this should be considered when adolescents are hospitalised with mental health conditions. [ABSTRACT FROM AUTHOR]

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1L613V/wt mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP+ astrocytes was significantly increased in the adult Raf1L613V/wt cortex and hippocampus relative to controls. OLIG2+ oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1L613V/wt mice mutants performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1L613V/wt mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function. [ABSTRACT FROM AUTHOR]

Chronic stress typically leads to deficits in fear extinction. However, when a delay occurs from the end of chronic stress and the start of fear conditioning (a "recovery"), rats show improved context-cue discrimination, compared to recently stressed rats or nonstressed rats. The infralimbic cortex (IL) is important for fear extinction and undergoes neuronal remodeling after chronic stress ends, which could drive improved context-cue discrimination. Here, glutamatergic IL neurons of Sprague-Dawley male rats were targeted for inhibition using inhibitory designer receptors exclusively activated by designer drugs (DREADDs) and daily injections of clozapine N-oxide (CNO) during a 21-day recovery period from chronic stress. Histological verification confirmed DREADDs in the IL with some spread to nearby medial prefrontal cortex (PFC) regions. CNO administration was then discontinued before fear conditioning started and behavioral testing thereafter so that behavioral assessments occurred without neuronal inhibition. Fear conditioning involved presenting male rats with three tone-foot shock pairings on 1 day, which was followed by 2 days of 15 tone-alone extinction sessions. Daily and repeated inhibition of mainly IL neurons during the 21-day recovery period did not disrupt fear learning or fear extinction in all groups (controls, stressed rats without a recovery, and stressed rats with a recovery). However, chronically stressed rats given a recovery and with DREADD activation showed impaired spontaneous recovery, indicating a failure to form a tone-foot shock association. The findings show that daily inhibition of mainly IL neurons prior to fear conditioning and extinction depends upon the changes that occur during the recovery period following the end of chronic stress., (© 2025 Judd et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: The 3xTg-AD transgenic mouse model of Alzheimer's disease (AD) is an important tool to investigate the relationship between development of pathological amyloid-β (Aβ) and tau, neuroinflammation, and cognitive impairments. Traditional behavioral tasks assessing aspects of learning and memory, such as mazes requiring spatial navigation, unfortunately suffer from several shortcomings, including the stress of human handling and not probing species-typical behavior. The automated IntelliCage system was developed to circumvent such issues by testing mice in a social environment while measuring multiple aspects of cognition. Water consumption can serve as a primary motivator for task engagement. Once animals adapt to the cage and can access water, mice can be subjected to operant tasks. Each of the four corners of a cage contains doors to manipulate access to water, visual LED cues, and a valve allowing administration of an air puff. Previously, we detected significant impairments in 3xTg-AD mice in the IntelliCage, however a high failure rate and genotypical differences in water motivation were observed., Methods: Here, we implemented an IntelliCage paradigm where mice underwent progressively more difficult reaction time tasks to assess attention and impulsivity, behaviors mediated by the prefrontal cortex. Mice were placed in the IntelliCage at 11.5 months of age, which corresponds with the presence of widespread pathology., Results: As the difficulty of the reaction time tasks increased, 3xTg-AD mice exhibited lower percent Correct Responses than NonTg. When implementing varying pre-cue durations, where animals are required to wait between the initiation of the trial and the LED turning on (which then requires a nose-poke to access water), 3xTg-AD mice prematurely nose-poked on trials requiring a longer delay before a second nose poke would allow water access, demonstrating heightened impulsivity. The presence of soluble and insoluble fractions of cortical Aβ40 and 42, and phosphorylated tau epitopes threonine 181 and serine 396 confirmed the presence of neuropathological hallmarks in 3xTg-AD mice., Conclusion: Together, this study describes a novel protocol that overcomes motivational differences and detects attention and impulsivity deficits in 3xTg-AD mice utilizing the IntelliCage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Judd, Winslow, McDonough, Mistry and Velazquez.)

Most Americans (∼90%) are deficient in dietary choline, an essential nutrient. Associations between circulating choline and pathological progression in Alzheimer's disease (AD) remain unknown. Here, we examined these associations and performed a metabolomic analysis in blood serum from severe AD, moderate AD, and healthy controls. Additionally, to gain mechanistic insight, we assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice. In humans, we found AD-associated reductions in choline, it's derivative acetylcholine (ACh), and elevated pro-inflammatory cytokine TNFα. Choline and ACh were negatively correlated with Plaque density, Braak stage, and TNFα, but positively correlated with MMSE and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were associated with choline levels. In mice, Ch-paralleled AD severe, but Ch+ was protective. In conclusion, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of dietary choline consumption to offset disease.