Systematic review of pharmacological treatments that reduce conditioned taste aversions in rodents: A potential animal model of pediatric feeding disorder and avoidant/restrictive food intake disorder (ARFID).

Avoidant/restrictive food intake disorder (ARFID) is diagnosed when food avoidance leads to clinically significant nutritional, weight/growth, or psychosocial impairment. As many as 81.5% of children and adolescents diagnosed with ARFID have a history of a medical condition associated with pain, fatigue, or malaise. ARFID is diagnosed and treatment begins after the medical condition is resolved but food avoidance remains. Effective treatment involves repeated exposure to eating food and related stimuli aimed at creating inhibitory learning to counteract learned fears and aversions. Treatment usually involves positive reinforcement of food approach behavior and escape extinction/response prevention to eliminate food avoidant behavior. To shed light on the neural mechanisms that may maintain ARFID and to identify candidate pharmacological treatments for adjuncts to behavioral interventions, this paper systematically reviews research on drug treatments that successfully reduce conditioned taste aversions (CTA) in animal models by disrupting reconsolidation or promoting extinction. The mechanism of action of these treatments, brain areas involved, and whether these CTA findings have been used to understand human eating behavior are assessed. Collectively, the results provide insight into possible neural mechanisms associated with resuming oral intake following CTA akin to the therapeutic goals of ARFID treatment and suggest that CTA animal models hold promise to facilitate the development of interventions to prevent feeding problems. The findings also reveal the need to investigate CTA reduction in juvenile and female animals and show that CTA is rarely studied to understand disordered human feeding even though CTA has been observed in humans and parallels many of the characteristics of rodent CTA.

Angiotensin II-Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats.

BACKGROUND: Heart failure (HF) is a debilitating disease affecting >64 million people worldwide. In addition to impaired cardiovascular performance and associated systemic complications, most patients with HF suffer from depression and substantial cognitive decline. Although neuroinflammation and brain hypoperfusion occur in humans and rodents with HF, the underlying neuronal substrates, mechanisms, and their relative contribution to cognitive deficits in HF remains unknown. METHODS: To address this critical gap in our knowledge, we used a well-established HF rat model that mimics clinical outcomes observed in the human population, along with a multidisciplinary approach combining behavioral, electrophysiological, neuroanatomical, molecular and systemic physiological approaches. RESULTS: Our studies support neuroinflammation, hypoperfusion/hypoxia, and neuronal deficits in the hippocampus of HF rats, which correlated with the progression and severity of the disease. An increased expression of AT1aRs (Ang II [angiotensin II] receptor type 1a) in hippocampal microglia preceded the onset of neuroinflammation. Importantly, blockade of AT1Rs with a clinically used therapeutic drug (Losartan), and delivered in a clinically relevant manner, efficiently reversed neuroinflammatory end points (but not hypoxia ones), resulting in turn in improved cognitive performance in HF rats. Finally, we show than circulating Ang II can leak and access the hippocampal parenchyma in HF rats, constituting a possible source of Ang II initiating the neuroinflammatory signaling cascade in HF. CONCLUSIONS: In this study, we identified a neuronal substrate (hippocampus), a mechanism (Ang II-driven neuroinflammation) and a potential neuroprotective therapeutic target (AT1aRs) for the treatment of cognitive deficits in HF.

Heart failure impairs mood and memory in male rats and down-regulates the expression of numerous genes important for synaptic plasticity in related brain regions.

Chronic heart failure (HF) is a serious disorder that afflicts more than 26 million patients worldwide. HF is comorbid with depression, anxiety and memory deficits that have serious implications for quality of life and self-care in patients who have HF. Still, there are few studies that have assessed the effects of severely reduced ejection fraction (≤40 %) on cognition in non-human animal models. Moreover, limited information is available regarding the effects of HF on genetic markers of synaptic plasticity in brain areas critical for memory and mood regulation. We induced HF in male rats and tested mood and anxiety (sucrose preference and elevated plus maze) and memory (spontaneous alternation and inhibitory avoidance) and measured the simultaneous expression of 84 synaptic plasticity-associated genes in dorsal (DH) and ventral hippocampus (VH), basolateral (BLA) and central amygdala (CeA) and prefrontal cortex (PFC). We also included the hypothalamic paraventricular nucleus (PVN), which is implicated in neurohumoral activation in HF. Our results show that rats with severely reduced ejection fraction recapitulate behavioral symptoms seen in patients with chronic HF including, increased anxiety and impaired memory in both tasks. HF also downregulated several synaptic-plasticity genes in PFC and PVN, moderate decreases in DH and CeA and minimal effects in BLA and VH. Collectively, these findings identify candidate brain areas and molecular mechanisms underlying HF-induced disturbances in mood and memory.