Societal costs and survival of patients with biopsy-verified non-alcoholic steatohepatitis: Danish nationwide register-based study.

INTRODUCTION AND OBJECTIVES: Studies on the societal burden of patients with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) are sparse. This study examined this question, comparing NAFLD with matched reference groups. MATERIALS AND METHODS: Nationwide Danish healthcare registers were used to include all patients (≥18 years) diagnosed with biopsy-verified NAFLD (1997-2021). Patients were classified as having simple steatosis or non-alcoholic steatohepatitis (NASH) with or without cirrhosis, and all matched with liver-disease free reference groups. Healthcare costs and labour market outcomes were compared from 5 years before to 11 years after diagnosis. Patients were followed for 25 years to analyse risk of disability insurance and death. RESULTS: 3,712 patients with biopsy-verified NASH (n = 1,030), simple steatosis (n = 1,540) or cirrhosis (n = 1,142) were identified. The average total costs in the year leading up to diagnosis was 4.1-fold higher for NASH patients than the reference group (EUR 6,318), 6.2-fold higher for cirrhosis patients and 3.1-fold higher for simple steatosis patients. In NASH, outpatient hospital contacts were responsible for 49 % of the excess costs (EUR 3,121). NASH patients had statistically significantly lower income than their reference group as early as five years before diagnosis until nine years after diagnosis, and markedly higher risk of becoming disability insurance recipients (HR: 4.37; 95 % CI: 3.17-6.02) and of death (HR: 2.42; 95 % CI: 1.80-3.25). CONCLUSIONS: NASH, simple steatosis and cirrhosis are all associated with substantial costs for the individual and the society with excess healthcare costs and poorer labour market outcomes.

Phencyclidine administration during neurodevelopment alters network activity in prefrontal cortex and hippocampus in adult rats.

Symptoms of schizophrenia have been linked to insults during neurodevelopment such as NMDA receptor (NMDAR) antagonist exposure. In animal models, this leads to schizophrenia-like behavioral symptoms as well as molecular and functional changes within hippocampal and prefrontal regions. The aim of this study was to determine how administration of the NMDAR antagonist phencyclidine (PCP) during neurodevelopment affects functional network activity within the hippocampus and medial prefrontal cortex (mPFC). We recorded field potentials in vivo after electrical brain stem stimulation and observed a suppression of evoked theta power in ventral hippocampus, while evoked gamma power in mPFC was enhanced in rats administered with PCP neonatally. In addition, increased gamma synchrony elicited by acute administration of the NMDAR antagonist MK-801 was exaggerated in neonatal PCP animals. These data suggest that NMDAR antagonist exposure during brain development alters functional networks within hippocampus and mPFC possibly contributing to the reported behavioral symptoms of this animal model of schizophrenia.NEW & NOTEWORTHY We show that insults with a NMDA receptor antagonist during neurodevelopment lead to suppressed evoked theta oscillations in ventral hippocampus in adult rats, while evoked gamma oscillations are enhanced and hypersensitive to an acute challenge with a NMDA receptor antagonist in prefrontal cortex. These observations reveal the significance of neurodevelopmental disturbances in the evolvement of schizophrenia-like symptoms and contribute to the understanding of the functional deficits underlying aberrant behavior in this disease.

Activation of prefrontal cortical parvalbumin interneurons facilitates extinction of reward-seeking behavior.

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility.

Memantine potentiates hippocampal θ oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties.

Memantine is an uncompetitive, low-affinity NMDA receptor antagonist clinically used for the treatment of cognitive deficits in moderate to severe Alzheimer's disease. Both neurophysiological and behavioral studies in rodents have suggested a beneficial effect of memantine on synaptic plasticity and learning performances. In the present study, we investigated the effect of memantine on pedonculopontine-elicited theta oscillations in the hippocampus of urethane anesthetized mice, a model shown to be sensitive to several pharmacological agents exhibiting cognitive-enhancing properties. We found that a low dose of memantine potentiated elicited theta power while a high dose was disruptive. The low dose of memantine used was shown to yield an unbound brain concentration well within the range of therapeutic concentrations reported in rodent brain extracellular fluid and human cerebrospinal fluid. For further comparison, the effect of another uncompetitive NMDA receptor antagonist with higher affinity, i.e. MK-801, was also investigated. MK-801 was at a low dose devoid of effect on elicited theta power, while a high dose, within the range of doses reported to induce cognitive deficits in a variety of hippocampal-dependent learning paradigms in mice, was found disruptive on elicited theta waves. Taken together, our results suggest that clinically relevant doses of memantine promote neuronal network synchronization in the hippocampus, which may represent an underlying mechanism for the reported cognitive-enhancing properties in both preclinical and clinical studies.

Combination of escitalopram and a 5-HT(1A) receptor antagonist selectively decreases the extracellular levels of dopamine in the nucleus accumbens relative to striatum through 5-HT(2C) receptor stimulation; suggestive of antipsychotic potential.

Serotonin 5-HT(2C) receptors are widely distributed throughout the brain located on GABAergic interneurons and afferent neurons in the ventral tegmental area and substantia nigra. Consequently, activation of this receptor modulates the dopaminergic neurotransmission. The antipsychotic potential of the combined treatment with escitalopram, in therapeutic relevant doses, and the 5-HT(1A) receptor antagonist, WAY-100635, has been evaluated by assessment of conditioned avoidance (CAR) behaviour and the use of microdialysis in freely moving rats. The combined treatment was found to decrease both CAR behaviour without affecting escape failures and the basal extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) acutely without affecting DA levels in the striatum, suggesting an antipsychotic-like effect with mesolimbic selectivity. The escitalopram/WAY-100635-induced changes in CAR behaviour and DA were prevented by pretreatment with the 5-HT(2C) receptor antagonist, SB242084, indicating that the effects are mediated by stimulation of the 5-HT(2C) receptor. Thus, indirect activation of the 5-HT(2C) receptor may induce antipsychotic-like effects. The observations on DA levels were in line with the findings made with the selective 5-HT(2C) receptor agonist, vabicaserin, which was also shown to produce a mesolimbic selective decrease in DA levels in the present study. In addition, it was demonstrated that escitalopram, in combination with the partial 5-HT(1A) agonist, (-)-pindolol, decreased basal DA levels in the NAc. A potential therapeutic effect could readily be assessed, since both escitalopram and (-)-pindolol are already on the market.

Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits.

In vivo optogenetic strategies have redefined our ability to assay how neural circuits govern behavior. Although acutely implanted optical fibers have previously been used in such studies, long-term control over neuronal activity has been largely unachievable. Here we describe a method to construct implantable optical fibers to readily manipulate neural circuit elements with minimal tissue damage or change in light output over time (weeks to months). Implanted optical fibers readily interface with in vivo electrophysiological arrays or electrochemical detection electrodes. The procedure described here, from implant construction to the start of behavioral experimentation, can be completed in approximately 2-6 weeks. Successful use of implantable optical fibers will allow for long-term control of mammalian neural circuits in vivo, which is integral to the study of the neurobiology of behavior.