Victoria A. Macht

Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: Effects of dietary restriction

Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA sequence (IRAS) that when injected into the hypothalamus selectively decreases IR signaling in hypothalamus, resulting in increased body weight, peripheral adiposity and plasma leptin levels. To test the hypothesis that this obesity/hyperleptinemic phenotype would impair hippocampal synaptic transmission, we examined short term potentiation (STP) and long term potentiation (LTP) in the hippocampus of rats that received the LV-IRAS construct or the LV-Control construct in the hypothalamus (hypo-IRAS and hypo-Con, respectively). Stimulation of the Schaffer collaterals elicits STP that develops into LTP in the CA1 region of hypo-Con rats; conversely, hypo-IRAS rats exhibit STP that fails to develop into LTP. To more closely examine the potential role of hyperleptinemia in these electrophysiological deficits, hypo-IRAS were subjected to mild food restriction paradigms that would either: 1) prevent the development of the obesity phenotype; or 2) reverse an established obesity phenotype in hypo-IRAS rats. Both of these paradigms restored LTP in the CA1 region and reversed the decreases in the phosphorylated/total ratio of GluA1 Ser845 AMPA receptor subunit expression observed in the hippocampus of hypo-IRAS rats. Collectively, these data support the hypothesis that obesity impairs hippocampal synaptic transmission and support the hypothesis that these deficits are mediated through the impairment of hippocampal leptin activity.

Repeated restraint stress-induced atrophy of glutamatergic pyramidal neurons and decreases in glutamatergic efflux in the rat amygdala are prevented by the antidepressant agomelatine.

Major depressive illness is among the most prevalent neuropsychiatric disorders and is associated with neuroplasticity deficits in limbic structures such as the amygdala. Since exposure to stressful life events is proposed to contribute to depressive illness, our recent studies examined the effects of stress on amygdalar neuroplasticity. These studies determined that repeated stress elicits deficits in glutamatergic activity in the amygdala, neuroplasticity deficits that can be prevented by some but not all antidepressants. In view of these observations, the goal of the current study was to determine the effects of repeated restraint stress (RRS) on the dendritic architecture of pyramidal neurons in the rat basolateral nucleus of the amygdala (CBL), as well as glutamate efflux in the CBL and central nucleus of the amygdala (CMX) via in vivo microdialysis. We also examined the ability of the antidepressant agomelatine to prevent RRS-induced neuroplasticity deficits. Compared with control rats, rats subjected to RRS exhibited atrophy of CBL pyramidal neurons, including decreases in total dendritic length, branch points, and dendritic complexity index. In addition, glutamate efflux was significantly reduced in the CMX of rats subjected to RRS, thereby identifying a potential neurochemical consequence of stress-induced dendritic atrophy of CBL pyramidal neurons. Lastly, an acute stress challenge increased corticosterone (CORT) levels in the CBL, suggesting that stress-induced increases in CORT levels may contribute to the neuroanatomical and neurochemical effects of RRS in the CBL. Importantly, these RRS-induced changes were prevented by daily agomelatine administration. These results demonstrate that the neuroanatomical and neurochemical properties of glutamatergic neurons in the rat amygdala are adversely affected by repeated stress and suggest that the therapeutic effects of agomelatine may include protection of structural and neurochemical plasticity in limbic structures like the amygdala.

Dietary restriction reverses obesity-induced anhedonia.

Obesity-induced changes in the metabolic and endocrine milieu elicit deficits in neuroplasticity, including increased risk for development of neuropsychiatric disorders such as depressive illness. We previously demonstrated that downregulation of hypothalamic insulin receptors (hypo-IRAS) elicits a phenotype that is consistent with features of the metabolic syndrome (MetS) and that rats with this phenotype exhibit deficits in neuronal plasticity, including depressive-like behaviors such as anhedonia. Since food restriction paradigms effectively inhibit obesity-induced neuroplasticity deficits, the aim of the current study was to determine whether food restriction could reverse obesity-induced anhedonia in hypo-IRAS rats. Compared to hypo-IRAS rats provided ad lib food access, food restriction paradigms that were initiated either prior to increases in body weight or following development of the MetS/obesity phenotype effectively restored sucrose intake in hypo-IRAS rats. Moreover, food restriction paradigms were able to prevent and reverse the changes in the endocrine/metabolic/inflammatory milieu observed in hypo-IRAS, such as increases in plasma leptin and triglyceride levels and increases in pro-inflammatory cytokines such as IL-1α, IL-6 and C-reactive protein (CRP). Collectively, these results demonstrate that obesity-induced anhedonia is a reversible process and identify some potential mechanistic mediators that may be responsible for co-morbid depression in obesity.

Leptin resistance and hippocampal behavioral deficits

The adipocyte-derived hormone leptin is an important regulator of body weight and metabolism through activation of brain leptin receptors expressed in regions such as the hypothalamus. Beyond these well described and characterized activities of leptin in the hypothalamus, it is becoming increasingly clear that the central activities of leptin extend to the hippocampus. Indeed, leptin receptors are expressed in the hippocampus where these receptors are proposed to mediate various aspects of hippocampal synaptic plasticity that ultimately impact cognitive function. This concept is supported by studies demonstrating that leptin promotes hippocampal-dependent learning and memory, as well as studies indicating that leptin resistance is associated with deficits in hippocampal-dependent behaviors and in the induction of depressive-like behaviors. The effects of leptin on cognitive/behavioral plasticity in the hippocampus may be regulated by direct activation of leptin receptors expressed in the hippocampus; additionally, leptin-mediated activation of synaptic networks that project to the hippocampus may also impact hippocampal-mediated behaviors. In view of these previous observations, the goal of this review will be to discuss the mechanisms through which leptin facilitates cognition and behavior, as well as to dissect the loci at which leptin resistance leads to impairments in hippocampal synaptic plasticity, including the development of cognitive deficits and increased risk of depressive illness in metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM).

Neuro-immune interactions across development: A look at glutamate in the prefrontal cortex.

Although the primary role for the immune system is to respond to pathogens, more recently, the immune system has been demonstrated to have a critical role in signaling developmental events. Of particular interest for this review is how immunocompetent microglia and astrocytes interact with glutamatergic systems to influence the development of neural circuits in the prefrontal cortex (PFC). Microglia are the resident macrophages of the brain, and astrocytes mediate both glutamatergic uptake and coordinate with microglia to respond to the general excitatory state of the brain. Cross-talk between microglia, astrocytes, and glutamatergic neurons forms a quad-partite synapse, and this review argues that interactions within this synapse have critical implications for the maturation of PFC-dependent cognitive function. Similarly, understanding developmental shifts in immune signaling may help elucidate variations in sensitivities to developmental disruptions.

Upregulation of orexin/hypocretin expression in aged rats: Effects on feeding latency and neurotransmission in the insular cortex

Aging is associated with changes in numerous homeostatic functions, such as food intake, that are thought to be mediated by the hypothalamus. Orexin/hypocretin neurons of the hypothalamus regulate several physiological functions, including feeding, sleep and wakefulness. Evidence from both clinical and animal studies supports the notion that aging is associated with loss or dysregulation of the orexin system. Here, we used virus-mediated gene transfer to manipulate expression of orexin peptides in young and aged rats and examined behavioral and neurochemical correlates of food intake in these animals. Aged rats showed slower feeding latencies when presented with palatable food compared to young control rats, and these deficits were ameliorated by upregulation of orexin expression. Similarly, young animals treated with a virus designed to decrease preproorexin expression showed longer feeding latencies reminiscent of aged control rats. Feeding was also associated with increased acetylcholine, glutamate and GABA efflux in insular cortex of young control animals. Orexin upregulation did not restore deficits in feeding-elicited release of these neurotransmitters in aged rats, but did enhance basal neurotransmitter levels which may have contributed to the behavioral correlates of these genetic manipulations. These studies demonstrate that age-related deficits in behavioral and neurochemical measures of feeding are likely to be mediated, in part, by the orexin system. Because these same neurotransmitter systems have been shown to underlie orexin effects on cognition, treatments which increase orexin function may have potential for improving both physiological and cognitive manifestations of certain age-related disorders.

Leptin resistance elicits depressive-like behaviors in rats

There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and include increased risk for development of neuropsychiatric co-morbidities such as depressive illness. The neurological consequences of obesity may develop as a continuum and involve a progression of pathological features which is initiated by leptin resistance. Leptin resistance is a hallmark feature of obesity, but it is unknown whether leptin resistance or blockage of leptin action is casually linked to the neurological changes which underlie depressive-like phenotypes. Accordingly, the aim of the current study was to examine whether chronic administration of a pegylated leptin receptor antagonist (Peg-LRA) elicits depressive-like behaviors in adult male rats. Peg-LRA administration resulted in endocrine and metabolic features that are characteristic of an obesity phenotype. Peg-LRA rats also exhibited increased immobility in the forced swim test, depressive-like behaviors that were accompanied by indices of peripheral inflammation. These results demonstrate that leptin resistance elicits an obesity phenotype that is characterized by peripheral immune changes and depressive-like behaviors in rats, supporting the concept that co-morbid obesity and depressive illness develop as a continuum resulting from changes in the peripheral endocrine and metabolic milieu.

Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood

&NA; Fetal Alcohol Syndrome (FAS) is associated with high rates of drug addiction in adulthood. One possible basis for increased drug use in this population is altered sensitivity to drug‐associated contexts. This experiment utilized a rat model of FASD to examine behavioral and neural changes in the processing of drug cues in adulthood. Alcohol was given by intragastric intubation to pregnant rats throughout gestation and to rat pups during the early postnatal period (ET group). Controls consisted of a non‐treated group (NC) and a pair‐fed group given the intubation procedure without alcohol (IC). On postnatal day (PD) 90, rats from all treatment groups were given saline, 0.3 mg/kg, 3.0 mg/kg, or 10.0 mg/kg cocaine pairings with a specific context in the conditioned place preference (CPP) paradigm. While control animals of both sexes showed cocaine CPP at the 3.0 and 10.0 mg/kg doses, ET females also showed cocaine CPP at 0.3 mg/kg. This was accompanied by a decrease in c‐Fos/GAD67 cells in the nucleus accumbens (NAc) shell and GAD67‐only cells in the NAc shell and PFC at this 0.3 mg/kg dose. ET males failed to show cocaine CPP at the 3.0 mg/kg dose. This was associated with an increase in c‐Fos only‐labeled cells in the NAc core and PFC at this 3.0 mg/kg dose. These results suggest that developmental alcohol exposure has a sexually‐dimorphic effect on cocaines conditioning effects in adulthood and the NAc. HighlightsDevelopmental alcohol exposure results in sexually dimorphic changes to drug cues.Alcohol‐exposed females exhibit CPP at lower doses of cocaine than controls.Data suggest decreases in GABAergic neurons in the NAc shell and PFC in ET‐females.

Pathophysiology in a model of Gulf War Illness: Contributions of pyridostigmine bromide and stress

During the Gulf War, prophylactic treatment with pyridostigmine bromide (PB) along with the stress of deployment may have caused unexpected alterations in neural and immune function, resulting in a host of cognitive deficits which have become clinically termed Gulf War Illness (GWI). In order to test this interaction between PB and stress, the following study used a rodent model of GWI to examine how combinations of repeated restraint stress and PB induced alterations of peripheral cholinesterase (ChE) activity, corticosterone (CORT) levels, and cytokines on the last day of treatment, and then 10 days and three months post-treatment. Results indicate that PB decreases ChE activity acutely but sensitizes it by three months post-treatment selectively in rats subjected to stress. Similarly, while stress increased CORT levels acutely, rats in the PB/stressed condition continued to exhibit elevations in CORT at the delayed time point, indicating that PB and stress interact to progressively disrupt homeostasis in several peripheral measures. Because memory deficits are also common in clinical populations with GWI, we examined the effects of PB and stress on contextual fear conditioning. PB exacerbates stress-induced impairments in contextual fear conditioning ten days post-treatment, but protects against stress-induced augmentation of contextual fear conditioning at three months post-treatment. Collectively, these results provide critical insight as to how PB and stress may interact to contribute to the pathophysiological progression of GWI.

Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective

The development of the organism is a critical variable which influences the magnitude, duration, and reversibility of the effects of chronic stress. Such factors are relevant to the prefrontal cortex (PFC), as this brain region is the last to mature, the first to decline, and is highly stress-sensitive. Therefore, this review will examine the intersection between the nervous system and immune system at glutamatergic synapses in the PFC across three developmental periods: adolescence, adulthood, and aging. Glutamatergic synapses are tightly juxtaposed with microglia and astrocytes, and each of these cell types exhibits their own developmental trajectory. Not only does chronic stress differentially impact each of these cell types across development, but chronic stress also alters intercellular communication within this quad-partite synapse. These observations suggest that developmental shifts in both neural and immune function across neurons, microglia, and astrocytes mediate shifting effects of chronic stress on glutamatergic transmission.