Search bioRxiv⌕ Search

bioRxiv · 10.1101/2024.12.17.628856

Missing what is right under your nose: failed appetitive and aversive audio-olfactory conditioning in humans

Abstract

The comparison of physiological mechanisms underlying appetitive and aversive conditioning is often challenging due to the involvement of stimuli from different modalities with potentially disparate effective mechanisms (e.g., pain stimuli versus monetary rewards). The olfactory system offers a unique opportunity to examine both types of conditioning in humans, as isointense odors can serve as comparably pleasant and unpleasant stimuli. To study physiological and behavioral responses during appetitive and aversive learning, we employed odors as unconditioned stimuli (US) in a within-subjects design, measuring various conditioned physiological responses including skin conductance, heart rate, pulse wave amplitude, respiration, fear-potentiated startle, postauricular reflex, facial electromyography as well as event-related potentials, and auditory steady-state responses (ASSR) derived from electroencephalography. We conducted four experiments with a total of 95 participants, presenting three neutral sounds paired with either a pleasant odor, unpleasant odor, or odorless air. The first experiment involved uninstructed participants and frequency-modulated conditioned stimuli (CS) for ASSR analysis. In the second experiment, we omitted the frequency modulation and startle probe. The third experiment included pre-experiment instruction on CS-US contingencies, while the fourth employed a delayed conditioning paradigm in contrast to the other three experiments. Our results revealed differences between CS+ and CS-only in the fear-potentiated startle response in Experiment 3. No other effects were found. The minimal or absent learning effects observed across multiple peripheral and neural physiological measures may be attributed to the extra-thalamic nature of olfactory pathways and the subsequent difficulty in forming associations with auditory stimuli. Impact statementIn a series of 4 experiments, we explored the neurophysiological differences between appetitive and aversive conditioning. Yet, none of the experiments showed effective conditioning. We hypothesize that the lack of learning effects is attributed to the inherent difficulty in forming associations between auditory and olfactory inputs.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Menger, N. S., Kotchoubey, B., Ohla, K., Pavlov, Y. G.. 2024-12-20. Missing what is right under your nose: failed appetitive and aversive audio-olfactory conditioning in humans. https://doi.org/10.1101/2024.12.17.628856

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Cofilin Suppresses Tau-Induced Defects in Dense-Core Granule Formation and Aβ-Induced Neurodegeneration

Intracellular neurofibrillary tangles formed from hyperphosphorylated tau and extracellular amyloid plaques containing aggregated A{beta}-peptides, specific cleavage products of the Amyloid Precursor Protein (APP), are the primary histopathological hallmarks of Alzheimers Disease (AD), the leading cause of dementia in humans. However, the initiating steps that lead to these pathologies and early neurodegeneration, and the mechanisms by which tau- and A{beta}-induced effects might be linked remain unclear. Using the prostate-like secondary cell (SC) in Drosophila, we recently showed that A{beta} modulates normal APP- and membrane-associated protein aggregation in the dense-core granule (DCG) compartments of the regulated secretory pathway by interfering with subsequent membrane:DCG dissociation. This disrupts endolysosomal trafficking and propagates the resulting endolysosomal defects to other cells that endocytose the secreted abnormal DCG proteins. Here we show that overexpressing human tau also disrupts DCG aggregation and membrane:DCG dissociation inside SC secretory compartments, leading to increased endolysosomal targeting of these compartments. In a genetic screen, we find that knockdown of cofilin, which encodes an actin-severing protein required for dynamic remodelling of microfilaments, generates a similar phenotype. Consistent with this, overexpression of Cofilin, which is known to suppress tau-induced neurodegeneration in flies, reduces tau-induced DCG defects in SCs. Indeed, we find that Cofilin overexpression also suppresses A{beta}-induced degeneration in the fly eye. We conclude that membrane:DCG aggregate dissociation in DCG compartments is disrupted by both tau- and A{beta}-induced genetic changes that are relevant to AD, and this partially involves inhibition of actin cytoskeleton dynamics. Increasing actin remodelling activity can suppress neurodegeneration induced by both tau and A{beta}, suggesting that this process provides an important functional link between them that might be targeted therapeutically.

neuroscience↗

Lactate Promotes an Anti-Inflammatory Phenotype in Activated Microglia

Microglial activation is a central component of neuroinflammatory responses in many brain pathologies. Increasing evidence indicates that microglial phenotype is tightly linked to cellular metabolism, with pro-inflammatory activation associated with enhanced glycolytic flux. Lactate, traditionally considered a metabolic substrate, has recently emerged as a signaling molecule capable of modulating immune responses. However, its direct impact on microglial inflammatory activation remains incompletely understood. In the present study, we investigated the effects of lactate on microglial phenotype under inflammatory conditions using primary rat microglial cultures stimulated with lipopolysaccharide (LPS). Microglial activation was assessed through the expression of phenotypic markers, cytokine production, and secreted chemokine profiles. LPS stimulation induced a strong pro-inflammatory response characterized by increased CD86 expression, elevated TNF-alpha secretion, and enhanced release of several pro-inflammatory chemokines. Post-treatment with sodium L-lactate significantly attenuated these inflammatory responses, reducing pro-inflammatory marker expression and cytokine secretion, while restoring the anti-inflammatory marker CD206. To explore the relevance of these findings in a pathological context, the effects of lactate were further examined in a neonatal rat model of hypoxia-ischemia. Sodium L-lactate administration after injury reduced microglial activation and promoted a shift toward an anti-inflammatory phenotype in cortical regions, whereas hippocampal microglia showed a more limited response. Together, these results demonstrate that lactate directly modulates microglial inflammatory activation and cytokine production in vitro and suggest that lactate-mediated metabolic signaling may contribute in vivo to the regulation of neuroinflammatory responses.

neuroscience↗

Different hippocampal subfield volumes predict source memory performance and general cognitive ability in an adult lifespan sample

Modest positive associations between episodic memory performance and whole hippocampal and hippocampal subfield volumes have been reported in numerous prior studies. A smaller number of studies have reported associations between hippocampal volume and performance on tests of non-mnemonic cognition. The present study examined whether these associations were evident in a lifespan sample of cognitively healthy adults. Of particular interest was whether any identified associations were sensitive to age, and whether associations between subfield volumes and mnemonic and non-mnemonic performance were subfield dependent. We acquired high-resolution T1- and T2-weighted structural images from 163 adults (18-87 years of age). Participants also undertook a comprehensive neuropsychological test battery and an in-scanner test of source memory. Principal components analysis was employed to reduce the neuropsychological test scores to 5 cognitive components. Two components reflected memory performance while the other three reflected different aspects of non-mnemonic cognition. Hippocampal subfields (Cornu Ammonis (CA)1, CA2-3, dentate gyrus (DG) and subiculum) were segmented and measured with the Automated Segmentation of Hippocampus Subfields (ASHS) package. Source memory performance was selectively associated across participants with CA2-3 volume. By contrast, both mnemonic and non-mnemonic component scores derived from the test battery were associated exclusively with the volume of the DG. All associations were age-invariant. The findings indicate that different cognitive domains can be dissociated by virtue of their associations with different hippocampal subfields. Of importance, these associations appear to be life-long and hence are unlikely to reflect individual differences in age-related decline in structural integrity.

neuroscience↗