Clinical Implications of Climate Change on US Emergency Medicine: Challenges and Opportunities.

The adverse influences of climate change are manifesting as health burdens relevant to clinical practice, affecting the very underpinnings of health and stressing the health care system. Emergency medicine is likely to bear a large burden, with its focus on urgent and emergency care, through its role as a safety-net provider for vulnerable populations and as a leader in disaster medicine. Clinically, climate change is affecting emergency medicine practice through the amplification of climate-related disease patterns and epidemiologic shifts for conditions diagnosed and treated in emergency departments (EDs), especially for vulnerable populations. In addition, climate-driven intensification of extreme weather is disrupting health care delivery in EDs and health care systems. Thus, there are significant opportunities for emergency medicine to lead the medical response to climate change through 7 key areas: clinical practice improvements, building resilient EDs and health care systems, adaptation and public health engagement, disaster preparedness, mitigation, research, and education. In the face of this growing health threat, systemwide preparation rooted in local leadership and responsiveness is necessary to efficiently and effectively care for our vulnerable communities.

Biologically predisposed learning and selective associations in amygdalar neurons.

Modern views on learning and memory accept the notion of biological constraints-that the formation of association is not uniform across all stimuli. Yet cellular evidence of the encoding of selective associations is lacking. Here, conditioned stimuli (CSs) and unconditioned stimuli (USs) commonly employed in two basic associative learning paradigms, fear conditioning and taste aversion conditioning, were delivered in a manner compatible with a functional cellular imaging technique (Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization [catFISH]) to identify biological constraints on CS-US convergence at the level of neurons in basolateral amygdala (BLA). Results indicate coincident Arc mRNA activation within BLA neurons after CS-US combinations that yield rapid, efficient learning, but not after CS-US combinations that do not.

Functional imaging of stimulus convergence in amygdalar neurons during Pavlovian fear conditioning.

BACKGROUND: Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS) and unconditioned stimulus (US) during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH) to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus. CONCLUSIONS/SIGNIFICANCE: Based on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.

Visualizing stimulus convergence in amygdala neurons during associative learning.

A central feature of models of associative memory formation is the reliance on information convergence from pathways responsive to the conditioned stimulus (CS) and unconditioned stimulus (US). In particular, cells receiving coincident input are held to be critical for subsequent plasticity. Yet identification of neurons in the mammalian brain that respond to such coincident inputs during a learning event remains elusive. Here we use Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH) to locate populations of neurons in the mammalian brain that respond to both the CS and US during training in a one-trial learning task, conditioned taste aversion (CTA). Individual neurons in the basolateral nucleus of the amygdala (BLA) responded to both the CS taste and US drug during conditioning. Coincident activation was not evident, however, when stimulus exposure was altered so as to be ineffective in promoting learning (backward conditioning, latent inhibition). Together, these data provide clear visualization of neurons in the mammalian brain receiving convergent information about the CS and US during acquisition of a learned association.

Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria.

The molecular mechanisms mediating stress-induced dysphoria in humans and conditioned place aversion in rodents are unknown. Here, we show that repeated swim stress caused activation of both kappa-opioid receptor (KOR) and p38 mitogen-activated protein kinase (MAPK) coexpressed in GABAergic neurons in the nucleus accumbens, cortex, and hippocampus. Sites of activation were visualized using phosphoselective antibodies against activated kappa receptors (KOR-P) and against phospho-p38 MAPK. Surprisingly, the increase in P-p38-IR caused by swim-stress exposure was completely KOR dependent; P-p38-IR did not increase in KOR(-/-) knock-out mice subjected to the same swim-paradigm or in wild-type mice pretreated with the KOR antagonist norbinaltorphimine. To understand the relationship between p38 activation and the behavioral effects after KOR activation, we administered the p38 inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (i.c.v.)] and found that it selectively blocked the conditioned place aversion caused by the kappa agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and the KOR-dependent swim stress-induced immobility while not affecting kappa-opioid analgesia or nonselectively affecting associative learning. We found that the mechanism linking KOR and p38 activation in vivo was consistent with our previous in vitro data suggesting that beta-arrestin recruitment is required; mice lacking G-protein-coupled receptor kinase 3 also failed to increase p-p38-IR after KOR activation in vivo, failed to show swim stress-induced immobility, or develop conditioned place aversion to U50488. Our results indicate that activation of p38 MAPK signaling by the endogenous dynorphin-kappa-opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.

5-HT(1B) receptors in nucleus accumbens efferents enhance both rewarding and aversive effects of cocaine.

Whether serotonin-1B (5-HT(1B)) receptor activation enhances or diminishes the reinforcing properties of psychostimulants remains unclear. We have previously shown that increased expression of 5-HT(1B) receptors in nucleus accumbens (NAcc) shell neurons sensitized rats to the locomotor-stimulating and rewarding properties of cocaine. In this study we further examined the contribution of 5-HT(1B) receptors on the effect of cocaine under conditions intended to selectively influence either conditioned place preference or avoidance (CPP or CPA, respectively). Viral-mediated gene transfer techniques were used to overexpress 5-HT(1B) receptors in medial NAcc shell medium spiny neurons projecting to the ventral tegmental area. Animals were then conditioned to associate place cues with the effects of either a low (5 mg/kg) or moderately high (20 mg/kg) dosage of cocaine immediately or 45 min after intraperitoneal cocaine administration. Animals with increased 5-HT(1B) expression showed cocaine-induced CPP immediately after administration of the low 5 mg/kg dose of cocaine, but a CPA 45 min after administration of the high 20 mg/kg dose. Control animals showed no preference at the 5 mg/kg dose and a significant preference at 20 mg/kg. Given this, we believe that increased 5-HT(1B) receptor activation in NAcc shell projection neurons intensifies both the rewarding and negative properties of cocaine use.

Polycose taste pre-exposure fails to influence behavioral and neural indices of taste novelty.

Taste novelty can strongly modulate the speed and efficacy of taste aversion learning. Novel sweet tastes enhance c-Fos-like immunoreactivity (FLI) in the central amygdala and insular cortex. The present studies examined whether this neural correlate of novelty extends to different taste types by measuring FLI signals after exposure to novel and familiar polysaccharide (Polycose) and salt (NaCl) tastes. Novel Polycose not only failed to elevate FLI expression in central amygdala and insular cortex, but also failed to induce stronger taste aversion learning than familiar Polycose. Novel NaCl, on the other hand, showed patterns of FLI activation and aversion learning similar to that of novel sweet tastes. Possible reasons for the resistance of Polycose to typical pre-exposure effects are discussed.