Metabolic hormones mediate cognition.

Recent biochemical and behavioural evidence indicates that metabolic hormones not only regulate energy intake and nutrient content, but also modulate plasticity and cognition in the central nervous system. Disruptions in metabolic hormone signalling may provide a link between metabolic syndromes like obesity and diabetes, and cognitive impairment. For example, altered metabolic homeostasis in obesity is a strong determinant of the severity of age-related cognitive decline and neurodegenerative disease. Here we review the evidence that eating behaviours and metabolic hormones-particularly ghrelin, leptin, and insulin-are key players in the delicate regulation of neural plasticity and cognition. Caloric restriction and antidiabetic therapies, both of which affect metabolic hormone levels can restore metabolic homeostasis and enhance cognitive function. Thus, metabolic hormone pathways provide a promising target for the treatment of cognitive decline.

Intergenerational effects of a paternal Western diet during adolescence on offspring gut microbiota, stress reactivity, and social behavior.

The global consumption of highly processed, calorie-dense foods has contributed to an epidemic of overweight and obesity, along with negative consequences for metabolic dysfunction and disease susceptibility. As it becomes apparent that overweight and obesity have ripple effects through generations, understanding of the processes involved is required, in both maternal and paternal epigenetic inheritance. We focused on the patrilineal effects of a Western-style high-fat (21%) and high-sugar (34%) diet (WD) compared to control diet (CD) during adolescence and investigated F0 and F1 mice for physiological and behavioral changes. F0 males (fathers) showed increased body weight, impaired glycemic control, and decreased attractiveness to females. Paternal WD caused significant phenotypic changes in F1 offspring, including higher body weights of pups, increased Actinobacteria abundance in the gut microbiota (ascertained using 16S microbiome profiling), a food preference for WD pellets, increased male dominance and attractiveness to females, as well as decreased behavioral despair. These results collectively demonstrate the long-term intergenerational effects of a Western-style diet during paternal adolescence. The behavioral and physiological alterations in F1 offspring provide evidence of adaptive paternal programming via epigenetic inheritance. These findings have important implications for understanding paternally mediated intergenerational inheritance, and its relevance to offspring health and disease susceptibility.

Functional dissociation of behavioral effects from acetylcholine and glutamate released from cholinergic striatal interneurons.

In the striatum, cholinergic interneurons (CINs) have the ability to release both acetylcholine and glutamate, due to the expression of the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter 3 (VGLUT3). However, the relationship these neurotransmitters have in the regulation of behavior is not fully understood. Here we used reward-based touchscreen tests in mice to assess the individual and combined contributions of acetylcholine/glutamate co-transmission in behavior. We found that reduced levels of the VAChT from CINs negatively impacted dopamine signalling in response to reward, and disrupted complex responses in a sequential chain of events. In contrast, diminished VGLUT3 levels had somewhat opposite effects. When mutant mice were treated with haloperidol in a cue-based task, the drug did not affect the performance of VAChT mutant mice, whereas VGLUT3 mutant mice were highly sensitive to haloperidol. In mice where both vesicular transporters were deleted from CINs, we observed altered reward-evoked dopaminergic signalling and behavioral deficits that resemble, but were worse, than those in mice with specific loss of VAChT alone. These results demonstrate that the ability to secrete two different neurotransmitters allows CINs to exert complex modulation of a wide range of behaviors.

Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short-term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long-lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36-44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain-derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety-like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba-1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro-BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long-lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal-dependent learning and memory in adolescence.

An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats.

Objectives: Excessive consumption of high fat and high sugar (HFHS) diets alters reward processing, behaviour, and changes gut microbiota profiles. Previous studies in gnotobiotic mice also provide evidence that these gut microorganisms may influence social behaviour. To further investigate these interactions, we examined the impact of the intermittent access to a HFHS diet on social behaviour, gene expression and microbiota composition in adolescent rats. Methods: Male rats were permitted intermittent daily access (2 h / day) to a palatable HFHS chow diet for 28 days across adolescence. Social interaction, social memory and novel object recognition were assessed during this period. Following testing, RT-PCR was conducted on hippocampal and prefrontal cortex (PFC) samples. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa in faecal samples. Results: We observed reduced social interaction behaviours, impaired social memory and novel object recognition in HFHS diet rats compared to chow controls. RT-PCR revealed reduced levels of monoamine oxidase A (Maoa), catechol-O-methyltransferase (Comt) and brain derived neurotrophic factor (Bdnf) mRNA in the PFC of HFHS diet rats. Faecal microbiota analysis demonstrated that the relative abundance of a number of specific bacterial taxa differed significantly between the two diet groups, in particular, Lachnospiraceae and Ruminoccoceae bacteria. Discussion: Intermittent HFHS diet consumption evoked physiological changes to the brain, particularly expression of mRNA associated with reward and neuroplasticity, and gut microbiome. These changes may underpin the observed alterations to social behaviours.

Assessing the impacts of daily Cannabis versus alcohol and methamphetamines on young Australians in youth AOD treatment.

BACKGROUND: Cannabis is the most widely used illicit substance by Australian young people, including those engaged with youth alcohol and other drug (AOD) systems. While recreational cannabis use in young people may be a developmental activity for some, for others, this usage becomes regular and be associated with poorer long term outcomes. This study reports on the rates of cannabis use and co-existing psychosocial complexity factors in the Youth Needs Census (2013 and 2016) where workers report on all clients in the youth AOD system, a cohort considered highly vulnerable. METHODS: Data was examined for two rounds of data collection for the Youth Needs Census, including 823 youth AOD service engaged young people in 2016 and 1000 AOD service engaged young people in 2013, to identify usage rates, psychosocial outcomes, and changes over time. RESULTS: Daily use of cannabis alone significantly exceeded daily usage rates for methamphetamines, alcohol, and cannabis used alongside other substances. Daily cannabis use was significantly associated with mental health problems, employment problems, education problems, family problems, and housing problems. Daily cannabis use was associated with most psychosocial complexity factors to the same extent as daily methamphetamine use and daily alcohol use, with daily cannabis users only showing lower incidence of the drug-related harm measure. Notably, daily cannabis use also increased from 2013 (47.5%) to 2016 (54.2%). CONCLUSIONS: It is imperative that the number of individuals using cannabis is considered alongside the severity of harm when assessing the social impact of this substance. Within cannabis users engaged with the youth AOD system, who often have high levels of psychosocial complexity, cannabis is used daily by a large proportion of these youths and may play a role in negatively impacting their lives.

Daily access to sucrose impairs aspects of spatial memory tasks reliant on pattern separation and neural proliferation in rats.

High sugar diets reduce hippocampal neurogenesis, which is required for minimizing interference between memories, a process that involves "pattern separation." We provided rats with 2 h daily access to a sucrose solution for 28 d and assessed their performance on a spatial memory task. Sucrose consuming rats discriminated between objects in novel and familiar locations when there was a large spatial separation between the objects, but not when the separation was smaller. Neuroproliferation markers in the dentate gyrus of the sucrose-consuming rats were reduced relative to controls. Thus, sucrose consumption impaired aspects of spatial memory and reduced hippocampal neuroproliferation.

Impaired fear extinction retention and increased anxiety-like behaviours induced by limited daily access to a high-fat/high-sugar diet in male rats: Implications for diet-induced prefrontal cortex dysregulation.

Anxiety disorders and obesity are both common in youth and young adults. Despite increasing evidence that over-consumption of palatable high-fat/high-sugar "junk" foods leads to adverse neurocognitive outcomes, little is known about the effects of palatable diets on emotional memories and fear regulation. In the present experiments we examined the effects of daily 2h consumption of a high-fat/high-sugar (HFHS) food across adolescence on fear inhibition and anxiety-like behaviour in young adult rats. Rats exposed to the HFHS diet exhibited impaired retention of fear extinction and increased anxiety-like behaviour in an emergence test compared to rats fed a standard diet. The HFHS-fed rats displayed diet-induced changes in prefrontal cortex (PFC) function which were detected by altered expression of GABAergic parvalbumin-expressing inhibitory interneurons and the stable transcription factor ΔFosB which accumulates in the PFC in response to chronic stimuli. Immunohistochemical analyses of the medial PFC revealed that animals fed the HFHS diet had fewer parvalbumin-expressing cells and increased levels of FosB/ΔFosB expression in the infralimbic cortex, a region implicated in the consolidation of fear extinction. There was a trend towards increased IBA-1 immunoreactivity, a marker of microglial activation, in the infralimbic cortex after HFHS diet exposure but expression of the extracellular glycoprotein reelin was unaffected. These findings demonstrate that a HFHS diet during adolescence is associated with reductions of prefrontal parvalbumin neurons and impaired fear inhibition in adulthood. Adverse effects of HFHS diets on the mechanisms of fear regulation may precipitate a vulnerability in obese individuals to the development of anxiety disorders.

Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity.

In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral control and high-order cognitive processes. Of particular concern is the fact that sugar intake is greatest in adolescence, an important neurodevelopmental period. We provided sucrose to rats when they were progressing through puberty and adolescence. Cognitive performance was assessed in adulthood on a task related to executive function, a rodent analog of the Stroop task. We found that sucrose-exposed rats failed to show context-appropriate responding during incongruent stimulus compounds presented at test, indicative of impairments in prefrontal cortex function. Sucrose exposed rats also showed deficits in an on object-in-place recognition memory task, indicating that both prefrontal and hippocampal function was impaired. Analysis of brains showed a reduction in expression of parvalbumin-immunoreactive GABAergic interneurons in the hippocampus and prefrontal cortex, indicating that sucrose consumption during adolescence induced long-term pathology, potentially underpinning the cognitive deficits observed. These results suggest that consumption of high levels of sugar-sweetened beverages by adolescents may also impair neurocognitive functions affecting decision-making and memory, potentially rendering them at risk for developing mental health disorders.

Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression.

Both obesity and over-consumption of palatable high fat/high sugar "cafeteria" diets in rats has been shown to induce cognitive deficits in executive function, attention and spatial memory. Adult male Sprague-Dawley rats were fed a diet that supplemented standard lab chow with a range of palatable foods eaten by people for 8 weeks, or regular lab chow. Memory was assessed using a trace fear conditioning procedure, whereby a conditioned stimulus (CS) is presented for 10s and then 30s after its termination a foot shock (US) is delivered. We assessed freezing to the CS (flashing light) in a neutral context, and freezing in the context associated with footshock. A dissociation was observed between levels of freezing in the context and to the CS associated with footshock. Cafeteria diet fed rats froze less than control chow fed rats in the context associated with footshock (P<0.01), indicating that encoding of a hippocampus-dependent context representation was impaired in these rats. Conversely, cafeteria diet fed rats froze more (P<0.05) to the CS than chow fed rats, suggesting that when hippocampal function was compromised the cue was the best predictor of footshock, as contextual information was not encoded. Dorsal hippocampal mRNA expression of inflammatory and neuroplasticity markers was analysed at the end of the experiment, 10 weeks of diet. Of these, mRNA expression of reelin, which is known to be important in long term potentiation and neuronal plasticity, was significantly reduced in cafeteria diet fed rats (P=0.003). This implicates reductions in hippocampal plasticity in the contextual fear memory deficits seen in the cafeteria diet fed rats.

A bout of voluntary running enhances context conditioned fear, its extinction, and its reconsolidation.

Three experiments used rats to examine the effect of a single bout of voluntary activity (wheel running) on the acquisition, extinction, and reconsolidation of context conditioned fear. In Experiment 1, rats provided with access to a wheel for 3 h immediately before or after a shocked exposure to a context froze more when tested in that context than rats provided with access to the wheels 6 h after the shocked exposure or rats not provided with access to the wheels. In Experiment 2, rats provided with access to the wheels immediately before or after a nonshocked exposure to the conditioned context froze less when tested in that context than rats provided with access to the wheels 6 h after the nonshocked exposure or rats not provided with access to the wheels. In Experiment 3, rats provided with access to wheels immediately after an extended nonshocked exposure to the conditioned context again froze less, whereas rats provided with access to the wheels after a brief nonshocked exposure froze more on the subsequent test than sedentary controls. These results show that a single bout of running can enhance acquisition, extinction, and reconsolidation of context conditioned fear.

Ventral tegmental dopamine dysregulation prevents appetitive memory destabilization.

Through the process of reconsolidation, memories can be updated to maintain their relevance. To reconsolidate, a memory must first be destabilized in a process that we have hypothesized is initiated by a prediction error signal. Here we demonstrate that dysregulation of ventral tegmental area (VTA) signaling, which is thought to mediate prediction errors, prevented the destabilization of an appetitive goal-tracking memory in rats. We additionally show that intra-VTA infusion of either the competitive NMDA antagonist AP5 or the noncompetitive NMDA antagonist MK-801 does not selectively disrupt reconsolidation, indicating that the VTA may not be an important neural locus of reconsolidation-related neural plasticity.

Microbiome depletion prior to repeat mild TBI differentially alters social deficits and prefrontal cortex plasticity in adolescent and adult rats.

Although aging, repeat mild traumatic brain injury (RmTBI), and microbiome modifications independently change social behavior, there has been no investigation into their cumulative effects on social behavior and neuroplasticity within the prefrontal cortex. Therefore, we examined how microbiome depletion prior to RmTBI affected social behavior and neuroplasticity in adolescent and adult rats. Play, temperament analysis, elevated plus maze, and the hot/cold plate assessed socio-emotional function. Analyses of perineuronal nets (PNNs) and parvalbumin (PV) interneurons was completed. Social-emotional deficits were more pronounced in adults, with microbiome depletion attenuating social behavior deficits associated with RmTBI in both age groups. Microbiome depletion increased branch length and PNN arborization within the PFC but decreased the overall number of PNNs. Adults and males were more vulnerable to RmTBI. Interestingly, microbiome depletion may have attenuated the changes to neuroplasticity and subsequent social deficits, suggesting that the microbiome is a viable, but age-specific, target for RmTBI therapeutics.

Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

Appetitive Pavlovian goal-tracking memories reconsolidate only under specific conditions.

Despite extensive evidence that appetitive memories undergo reconsolidation, two notable failures to observe reconsolidation have been reported: instrumental responding and goal-tracking. However, these studies do not provide conclusive evidence for a lack of memory reconsolidation due to the numerous boundary conditions that dictate whether a memory will undergo reconsolidation. In this study we sought to reexamine reconsolidation in an appetitive, Pavlovian conditioned approach procedure and the behavioral boundary conditions within which memories are destabilized and reconsolidated. This study demonstrated that a Pavlovian goal-tracking memory, previously thought to be resistant to destabilization, will undergo memory reconsolidation under discrete conditions that favor reconsolidation as opposed to extinction, and that this is dependent on the amount of training rats received. With restricted training, systemic administration of MK-801 impaired memory extinction. In contrast, with more extended training, MK-801 administration impaired memory reconsolidation. We also demonstrate that behavioral boundary conditions that exist for appetitive memory reconsolidation are much more complex than simple parametric calculations. Moreover, extinction per se is not a boundary on reconsolidation, in that MK-801 also has no behavioral effect under some conditions.

Cortical Gyrification Morphology in Adult Males with Mild Traumatic Brain Injury.

Cortical gyrification, as a specific measure derived from magnetic resonance imaging, remains understudied in mild traumatic brain injury (mTBI). Local gyrification index (lGI) and mean curvature are related measures indexing the patterned folding of the cortex,ml which reflect distinct properties of cortical morphology and geometry. Using both metrics, we examined cortical gyrification morphology in 59 adult males with mTBI (n = 29) versus those without (n = 30) mTBI in the subacute phase of injury (between 2 weeks and 3 months). The effect of IQ on lGI and brain-symptom relations were also examined. General linear models revealed greater lGI in mTBI versus controls in the frontal lobes bilaterally, but reduced lGI in mTBI of the left temporal lobe. An age-related decrease in lGI was found in numerous areas, with no significant group-by-age interaction effects observed. Including other factors (i.e., mTBI severity, symptoms, and IQ) in the lGI model yielded similar results with few exceptions. Mean curvature analyses depicted a significant group-by-age interaction with the absence of significant main effects of group or age. Our results suggest that cortical gyrification morphology is adversely affected by mTBI in both frontal and temporal lobes, which are thought of as highly susceptible regions to mTBI. These findings contribute to understanding the effects of mTBI on neuromorphological properties, such as alterations in cortical gyrification, which reflect underlying microstructural changes (i.e., apoptosis, neuronal number, or white matter alterations). Future studies are needed to infer causal relationships between micro- and macrostructural changes after an mTBI and investigate potential sex differences.

Nutrition, anxiety and hormones. Why sex differences matter in the link between obesity and behavior.

Obesity and mood disorders are two of the most serious health issues of modern times. These health conditions are often linked, with obesity acting both as a cause and consequence of anxiety and depression. Although sex differences in the relationship between obesity and mood disorders are observed in clinical populations, the relative influence of biology versus societal conditioning is unclear. In part, this is because sex effects are rarely examined in the animal models used to derive our understanding of basic biological mechanisms. Due to the perceived confounding nature of hormonal fluctuations in females, rodent studies examining nutritional effects on behavioral responses are typically restricted to males. Yet, hormones play an important role in mediating effects of diet on behavior. In this mini-review, we outline interactions between obesity, hormones and the brain to illustrate the importance of considering sex-specific effects in studies of nutritional effects on behavior. We highlight the need for a more nuanced understanding of how dietary factors influence these relationships, arguing that such knowledge will help improve clinical health outcomes in the management of both obesity and mood disorders.

Synchronizing our clocks as we age: the influence of the brain-gut-immune axis on the sleep-wake cycle across the lifespan.

The microbes that colonize the small and large intestines, known as the gut microbiome, play an integral role in optimal brain development and function. The gut microbiome is a vital component of the bidirectional communication pathway between the brain, immune system, and gut, also known as the brain-gut-immune axis. To date, there has been minimal investigation into the implications of improper development of the gut microbiome and the brain-gut-immune axis on the sleep-wake cycle, particularly during sensitive periods of physical and neurological development, such as childhood, adolescence, and senescence. Therefore, this review will explore the current literature surrounding the overlapping developmental periods of the gut microbiome, brain, and immune system from birth through to senescence, while highlighting how the brain-gut-immune axis affects the maturation and organization of the sleep-wake cycle. We also examine how a dysfunction to either the microbiome or the sleep-wake cycle negatively affects the bidirectional relationship between the brain and gut, and subsequently the overall health and functionality of this complex system. Additionally, this review integrates therapeutic studies to demonstrate when dietary manipulations, such as supplementation with probiotics and prebiotics, can modulate the gut microbiome to enhance the health of the brain-gut-immune axis and optimize our sleep-wake cycle.