Basolateral amygdala to posterior piriform cortex connectivity ensures precision in learned odor threat.

Odor perception can both evoke emotional states and be shaped by emotional or hedonic states. The amygdala complex plays an important role in recognition of, and response to, hedonically valenced stimuli, and has strong, reciprocal connectivity with the primary olfactory (piriform) cortex. Here, we used differential odor-threat conditioning in rats to test the role of basolateral amygdala (BLA) input to the piriform cortex in acquisition and expression of learned olfactory threat responses. Using local field potential recordings, we demonstrated that functional connectivity (high gamma band coherence) between the BLA and posterior piriform cortex (pPCX) is enhanced after differential threat conditioning. Optogenetic suppression of activity within the BLA prevents learned threat acquisition, as do lesions of the pPCX prior to threat conditioning (without inducing anosmia), suggesting that both regions are critical for acquisition of learned odor threat responses. However, optogenetic BLA suppression during testing did not impair threat response to the CS+ , but did induce generalization to the CS-. A similar loss of stimulus control and threat generalization was induced by selective optogenetic suppression of BLA input to pPCX. These results suggest an important role for amygdala-sensory cortical connectivity in shaping responses to threatening stimuli.

Good scents: A short road from olfaction to satisfaction.

We rapidly classify odors as pleasant or aversive, but the brain circuits underlying how odors motivate approach and avoidance responses are largely unknown. New research describes a direct path from the olfactory bulb to ventral striatum driving odor-mediated reward.

Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories.

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.

Behavioral and Neurobiological Convergence of Odor, Mood and Emotion: A Review.

The affective state is the combination of emotion and mood, with mood reflecting a running average of sequential emotional events together with an underlying internal affective state. There is now extensive evidence that odors can overtly or subliminally modulate mood and emotion. Relying primarily on neurobiological literature, here we review what is known about how odors can affect emotions/moods and how emotions/moods may affect odor perception. We take the approach that form can provide insight into function by reviewing major brain regions and neural circuits underlying emotion and mood, and then reviewing the olfactory pathway in the context of that emotion/mood network. We highlight the extensive neuroanatomical opportunities for odor-emotion/mood convergence, as well as functional data demonstrating reciprocal interactions between these processes. Finally, we explore how the odor- emotion/mood interplay is, or could be, used in medical and/or commercial applications.

Odor Identification in Rats: Behavioral and Electrophysiological Evidence of Learned Olfactory-Auditory Associations.

The ability to recognize and identify a smell is highly dependent on multisensory context and expectation, for example, hearing the name of the odor source. Here, we develop a novel auditory-odor association task in rats, wherein the animal learns that a specific auditory tone, when associated with a specific odor, predicts reward (Go signal), whereas the same tone associated with a different odor, or vice versa, is not (No-Go signal). The tone occurs prior to the onset of the odor, allowing physiological analyses of sensory-evoked local field potential (LFP) activity to each stimulus in primary auditory cortex and anterior piriform cortex (aPCX). In trained animals that have acquired the task, both auditory and subsequent olfactory cues activate ß band oscillations in both the auditory cortex and PCX, suggesting multisensory integration. Naive animals show no such multisensory responses, suggesting the response is learned. In addition to the learned multisensory evoked responses, functional connectivity between auditory cortex and PCX, as assessed with spectral coherence and phase lag index (PLI), is enhanced. Importantly, both the multi-sensory evoked responses and the functional connectivity are context-dependent. In trained animals, the same auditory stimuli presented in the home cage evoke no responses in auditory cortex or PCX, and functional connectivity between the sensory cortices is reduced. Together, the results demonstrate how learning and context shape the expression of multisensory cortical processing. Given that odor identification impairment is associated with preclinical dementia in humans, the mechanisms suggested here may help develop experimental models to assess effects of neuropathology on behavior.

Human Apolipoprotein E Genotype Differentially Affects Olfactory Behavior and Sensory Physiology in Mice.

Apolipoprotein E (ApoE) is an important lipid carrier in both the periphery and the brain. The ApoE ε4 allele (ApoE4) is the single most important genetic risk-factor for Alzheimer's disease (AD) while the ε2 allele (ApoE2) is associated with a lower risk of AD-related neurodegeneration compared to the most common variant, ε3 (ApoE3). ApoE genotype affects a variety of neural circuits; however, the olfactory system appears to provide early biomarkers of ApoE genotype effects. Here, we directly compared olfactory behavior and olfactory system physiology across all three ApoE genotypes in 6-month- and 12-month-old mice with targeted replacement for the human ApoE2, ApoE3, or ApoE4 genes. Odor investigation and habituation were assessed, along with, olfactory bulb and piriform cortical local field potential activity. The results demonstrate that while initial odor investigation was unaffected by ApoE genotype, odor habituation was impaired in E4 relative to E2 mice, with E3 mice intermediate in function. There was also significant deterioration of odor habituation from 6 to 12 months of age regardless of the ApoE genotype. Olfactory system excitability and odor responsiveness were similarly determined by ApoE genotype, with an ApoE4 > ApoE3 > ApoE2 excitability ranking. Although motivated behavior is influenced by many processes, hyper-excitability of ApoE4 mice may contribute to impaired odor habituation, while hypo-excitability of ApoE2 mice may contribute to its protective effects. Given that these ApoE mice do not have AD pathology, our results demonstrate how ApoE affects the olfactory system at early stages, prior to the development of AD.

Lentivirus-mediated chronic expression of dominant-negative CREB in the dorsal hippocampus impairs memory for place learning and contextual fear conditioning.

Extensive research has shown that the transcription factor CREB has an important role during memory formation. In the present study, we tested a new method for chronic, stable expression of a dominant-negative form of CREB (mCREB) in the dorsal hippocampus using lentiviral vectors. In specific, we tested whether lentivirus-mediated chronic expression of mutant CREB impairs memory for two hippocampus-dependent tasks - place training in the water maze and contextual fear conditioning. Two weeks following intra-hippocampal infusion, experimental (mCREB) and control (LacZ and saline) rats were trained for 30 trials in one session on a place task in a water plus-maze and tested for an additional 30 trials on day 2 and on day 7. On day 8, all rats were trained on a contextual fear conditioning task and tested 24h later. For place learning, there was no difference between treatment groups on day 1, indicating that treatment with the lentiviral vectors did not alter performance or acquisition of the task. In comparisons with controls, mCREB-treated rats were not significantly impaired on day 2, overall, but they showed significant impairment on day 7. Contextual fear memory was impaired in mCREB-infused rats in comparison with controls. At the end of the experiment, total CREB and phosphorylated CREB protein were measured by western blot. Levels of total CREB were increased by approximately 40% among mCREB-treated rats in comparisons with controls, whereas levels of pCREB did not differ between groups, suggesting that the treatment caused significant expression of mCREB. In addition, mCREB infused rats showed a significant reduction in the pCREB to CREB ratio in comparison with controls, suggesting that the memory deficit seen in mCREB rats is most likely due to disruption of gene regulation caused by expression of mutant CREB. Taken together, the present results show that lentivirus expressing mCREB can be used to effectively alter CREB function within the hippocampus and that the treatment impairs memory for hippocampus-dependent tasks.

The orbitofrontal cortex is not necessary for acquisition or remote recall of socially transmitted food preferences.

A role for prefrontal cortex has been proposed in systems consolidation of memory. The current study examined the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) in rats on acquisition and remote recall of socially transmitted food preferences (STFP). Subjects received excitotoxic lesions of the OFC, and they were trained on two food preferences. They were tested 1h after the first training session to determine the effect of the lesion on acquisition. The following day, they were trained on a second preference and tested 10 days later to determine the effect of the lesion on remote recall. OFC lesions did not impair either STFP acquisition or remote recall in comparisons with sham-operated animals. In addition, a subset of animals underwent odor discrimination and reversal training. Consistent with previous reports, subjects with OFC lesions required more trials to reach criterion and made more errors during reversal training than did sham-operated animals. Taken together, the results of the present study indicate that the orbitofrontal cortex is not necessary for acquisition or systems consolidation of socially transmitted food preferences.