Severity of autism and fear conditioning! (histamine, adrenaline, glutamate...)

[Guest guest]

Only high-functioning kids studied here. They found that the severity of their autism, esp social functioning, was related to the their fear conditioning (ie with how much fear/anxiety they react to environment).

This is very interesting because fear conditioning is closely linked to adrenergic/sympathetic system, GABA/glutamate, AND also to levels of histamine and to functioning of serotonin receptors, see below.

Super interesting and matches our anecdotal experience so far

Better fear conditioning is associated with reduced symptom severity in autism spectrum disorders

Evidence from behavioral and neuroimaging studies suggest that atypical amygdala function plays a critical role in the development of autism spectrum disorders (ASD). The handful of psychophysiological studies examining amygdala function in ASD using classical fear conditioning paradigms have yielded discordant results. We recorded skin conductance response (SCR) during a simple discrimination conditioning task in 30 children and adolescents (ages 8–18) diagnosed with high-functioning ASD and 30 age- and IQ-matched, typically developing controls. SCR response in the ASD group was uniquely and positively associated with social anxiety; and negatively correlated with autism symptom severity, in particular with social functioning. Fear conditioning studies have tremendous potential to aid understanding regarding the amygdale's role in the varied symptom profile of ASD. Our data demonstrate that such studies require careful attention to task-specific factors, including task complexity; and also to contributions of dimensional, within-group factors that contribute to ASD heterogeneity. South M et al, Autism Res2011,4:xxx–xxx. © 2011 http://www.ncbi.nlm.nih.gov/pubmed/21905243

Novelty-induced arousal enhances memory for cued classical fear conditioning: Interactions between peripheral adrenergic and brainstem glutamatergic systems

.... The findings demonstrate that novelty-induced arousal or increasing sympathetic activity with epinephrine in pre- The development of new associations following learning is mediated in part by increased phosphorylation of cAMP response element binding protein (CREB) and subsequent CRE-mediated gene expression exposed animals enhances memory through adrenergic mechanisms initiated in the periphery and transmitted centrally ...

.... Autonomic indices of sympathetic activity, including skin conductance, cardiac output, and circulating concentrations of the adrenal hormones corticosterone and epinephrine, are all elevated by presenting humans or animals with novel stimuli or after allowing free exploration in an unfamiliar environment the vagus/NTS complex....

.... Findings from study 3 revealed that pre-exposed subjects given epinephrine post-conditioning exhibited a significantly greater percentage of freezing behavior during tone-only presentations on a 48-h retention test than did pre-exposed controls. The epinephrine-induced memory enhancement reflected in a higher percentage of freezing behavior was attenuated by interrupting impulse flow between the vagus nerve and the brainstem by blocking postsynaptic glutamate receptors in the NTS.

.... arousal-induced changes in peripheral autonomic functioning involving elevated heart rate, increased discharge along vagal nerve fibers, and blood pressure are significantly reduced by blocking peripheral â-adrenergic receptors

.... Consistent with these findings, experiment 2 showed that blocking glutamate receptors in the NTS with the antagonist CNQX attenuates the memory improvement observed by conditioning animals in an unfamiliar context. ... Findings from this experiment demonstrated that novelty-induced arousal enhancement in memory is attenuated when synaptic communication between vagal afferents and brainstem neurons in the NTS are interrupted.

.... Overall, findings from experiments 1 and 2 suggest novelty-induced arousal affects mnemonic processes by influencing peripheral hormone release and subsequent activation of the vagal/NTS complex ... Findings from experiment 3 suggest that memory enhancement observed in response to novelty-induced arousal may involve peripheral hormonal secretion. This study demonstrated that increasing peripheral sympathetic output with epinephrine injections significantly enhanced the marginal levels of fear conditioning.

.... Given the mounting evidence that novelty and peripheral adrenergic mechanisms work in concert to strengthen synaptic connections, the current findings underscore the importance of signaling between the vagus and NTS complex in mediating the beneficial consequences of emotional arousal on memory. http://learnmem.cshlp.org/content/16/10/625.long

then also this:

The physiology of brain histamine.

.... The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed. http://www.ncbi.nlm.nih.gov/pubmed/11164999

The H1- and H2-histamine blockers chlorpheniramine and ranitidine applied to the nucleus basalis magnocellularis region modulate anxiety and reinforcement related processes.

http://www.ncbi.nlm.nih.gov/pubmed/9833631

GABA and histamine interaction in the basolateral amygdala of rats in the plus-maze test of anxiety-like behaviors.

http://www.ncbi.nlm.nih.gov/pubmed/18477857

D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine.

http://www.ncbi.nlm.nih.gov/pubmed/21628344

5-HT2- and D1-mechanisms of the basolateral nucleus of the amygdala enhance conditioned fear and impair unconditioned fear.

http://www.ncbi.nlm.nih.gov/pubmed/17126419

The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatmentWe found that acute administration of the SSRI citalopram enhanced acquisition, whereas chronic treatment reduced the acquisition of auditory fear conditioning. ... Our findings with citalopram are consistent with the clinical effects of SSRI treatment seen in patients with anxiety disorders, in which anxiety is often increased during early stages of treatment and decreased after several weeks of treatment. http://www.ncbi.nlm.nih.gov/pubmed/15184036