Search

Odors are key signals for guiding spatial behaviors such as foraging and navigation in rodents. Recent findings reveal that odor representations in the piriform cortex (PCx) also encode spatial context information. However, the brain origins of this information and its integration into PCx microcircuitry remain unclear. This study investigates the lateral entorhinal cortex (LEC) as a potential source of spatial contextual information affecting the PCx microcircuit and its olfactory responses. Using mice brain slices, we performed patch-clamp recordings on superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to observe their impact on PCx activity. Results show that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons due to higher monosynaptic connectivity. LEC inputs also differentially affect inhibitory circuits, activating PV while suppressing SOM interneurons. Studying the interaction between LEC inputs and sensory signals from the lateral olfactory tract (LOT) revealed that simultaneous LEC and LOT activation increases spiking in SP and DP neurons, with DP neurons showing a sharpened response due to LEC-induced inhibition that suppresses delayed LOT-evoked spikes. This suggests a regulatory mechanism where LEC inputs inhibit recurrent activity by activating PV interneurons. Our findings demonstrate that LEC afferents reconfigure PCx activity, aiding the understanding of how odor objects form within the PCx by integrating olfactory and nonolfactory information., Competing Interests: Competing interests statement:The authors declare no competing interest.

A core function of the olfactory system is to determine the valence of odors. In humans, central processing of odor valence perception has been shown to take form already within the olfactory bulb (OB), but the neural mechanisms by which this important information is communicated to, and from, the olfactory cortex (piriform cortex, PC) are not known. To assess communication between the 2 nodes, we simultaneously measured odor-dependent neural activity in the OB and PC from human participants while obtaining trial-by-trial valence ratings. By doing so, we could determine when subjective valence information was communicated, what kind of information was transferred, and how the information was transferred (i.e., in which frequency band). Support vector machine (SVM) learning was used on the coherence spectrum and frequency-resolved Granger causality to identify valence-dependent differences in functional and effective connectivity between the OB and PC. We found that the OB communicates subjective odor valence to the PC in the gamma band shortly after odor onset, while the PC subsequently feeds broader valence-related information back to the OB in the beta band. Decoding accuracy was better for negative than positive valence, suggesting a focus on negative valence. Critically, we replicated these findings in an independent data set using additional odors across a larger perceived valence range. Combined, these results demonstrate that the OB and PC communicate levels of subjective odor pleasantness across multiple frequencies, at specific time points, in a direction-dependent pattern in accordance with a two-stage model of odor processing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nordén et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca 2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca 2+ influx evoked by high K + solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca 2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The anatomy of the human piriform cortex (PC) is poorly understood. We used a bimodal connectivity-based-parcellation approach to investigate subregions of the PC and its connectional differentiation from the amygdala. One hundred (55 % female) genetically unrelated subjects from the Human Connectome Project were included. A region of interest (ROI) was delineated bilaterally covering PC and amygdala, and functional and structural connectivity of this ROI with the whole gray matter was computed. Spectral clustering was performed to obtain bilateral parcellations at granularities of k = 2-10 clusters and combined bimodal parcellations were computed. Validity of parcellations was assessed via their mean individual-to-group similarity per adjusted rand index (ARI). Individual-to-group similarity was higher than chance in both modalities and in all clustering solutions. The amygdala was clearly distinguished from PC in structural parcellations, and olfactory amygdala was connectionally more similar to amygdala than to PC. At higher granularities, an anterior and ventrotemporal and a posterior frontal cluster emerged within PC, as well as an additional temporal cluster at their boundary. Functional parcellations also showed a frontal piriform cluster, and similar temporal clusters were observed with less consistency. Results from bimodal parcellations were similar to the structural parcellations. Consistent results were obtained in a validation cohort. Distinction of the human PC from the amygdala, including its olfactory subregions, is possible based on its structural connectivity alone. The canonical fronto-temporal boundary within PC was reproduced in both modalities and with consistency. All obtained parcellations are freely available., Competing Interests: Declaration of competing interest FZ- None related to this work. Felix Zahnert has participated in a seminar on complex epilepsies funded by UCB. UK-None related to this work. Urs Kleinholdermann has participated in a DBS course industry funded by Boston Scientific Corp. DJP- None related to this work. David Pedrosa has received honoraria for speaking at symposia sponsored by Boston Scientific Corp, Medtronic, AbbVie Inc, Zambon and Esteve Pharmaceuticals GmbH. He has received honoraria as a consultant for Boston Scientific Corp and Bayer, and has received a grant from Boston Scientific Corp for a project entitled "Sensor-based optimisation of Deep Brain Stimulation settings in Parkinson's disease" (COMPARE-DBS). David Pedrosa's institution, not David Pedrosa himself, has received funding from the JNPD, the Horizon 2020 programme, the Parkinson's Foundation and, finally, David Pedrosa has been reimbursed for travel expenses to attend congresses by Esteve Pharmaceuticals GmbH and Boston Scientific Corp. LT- None related to this work. Between February 2018 and March 2023, Lars Timmermann received occasional payments as a consultant for Boston Scientific and also received honoraria as a speaker on symposia sponsored by UCB, Desitin, Boston Scientific, AbbVIE, Novartis, GlaxoSmithKline, Neuraxpharm, the Movement Disorders Society and DIAPLAN. The institution of Lars Timmermann, not Lars Timmermann personally received funding by Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, the Otto-Loewi-Foundation and the Deutsche Parkinson Vereinigung. Neither Lars Timmermann nor any member of his family holds stocks, stock options, patents, or financial interests in any of the above‐mentioned companies or their competitors. Lars Timmermann serves as the president of the German Neurological Society without any payment or any income. SK- None related to this work. Susanne Knake received consultant fees or speaker's honoraria from Arvelle, Bial, Epilog, Desitin, Precisis, UCB, and Zogenix. The other authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Olfactory perception depends not only on olfactory inputs but also on semantic context. Although multi-voxel activity patterns of the piriform cortex, a part of the primary olfactory cortex, have been shown to represent odor perception, it remains unclear whether semantic contexts modulate odor representation in this region. Here, we investigated whether multi-voxel activity patterns in the piriform cortex change when semantic context modulates odor perception and, if so, whether the modulated areas communicate with brain regions involved in semantic and memory processing beyond the piriform cortex. We also explored regional differences within the piriform cortex, which are influenced by olfactory input and semantic context. We used 2 × 2 combinations of word labels and odorants that were perceived as congruent and measured piriform activity with a 1-mm isotropic resolution using 7T MRI. We found that identical odorants labeled with different words were perceived differently. This labeling effect was observed in multi-voxel activity patterns in the piriform cortex, as the searchlight decoding analysis distinguished identical odors with different labels for half of the examined stimulus pairs. Significant functional connectivity was observed between parts of the piriform cortex that were modulated by labels and regions associated with semantic and memory processing. While the piriform multi-voxel patterns evoked by different olfactory inputs were also distinguishable, the decoding accuracy was significant for only one stimulus pair, preventing definitive conclusions regarding the locational differences between areas influenced by word labels and olfactory inputs. These results suggest that multi-voxel patterns of piriform activity can be modulated by semantic context, possibly due to communication between the piriform cortex and the semantic and memory regions., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Rodents can learn from exposure to rewarding odors to make better and quicker decisions. The piriform cortex is thought to be important for learning complex odor associations; however, it is not understood exactly how it learns to remember discriminations between many, sometimes overlapping, odor mixtures. We investigated how odor mixtures are represented in the posterior piriform cortex (pPC) of mice while they learn to discriminate a unique target odor mixture against hundreds of nontarget mixtures. We find that a significant proportion of pPC neurons discriminate between the target and all other nontarget odor mixtures. Neurons that prefer the target odor mixture tend to respond with brief increases in firing rate at odor onset compared to other neurons, which exhibit sustained and/or decreased firing. We allowed mice to continue training after they had reached high levels of performance and find that pPC neurons become more selective for target odor mixtures as well as for randomly chosen repeated nontarget odor mixtures that mice did not have to discriminate from other nontargets. These single unit changes during overtraining are accompanied by better categorization decoding at the population level, even though behavioral metrics of mice such as reward rate and latency to respond do not change. However, when difficult ambiguous trial types are introduced, the robustness of the target selectivity is correlated with better performance on the difficult trials. Taken together, these data reveal pPC as a dynamic and robust system that can optimize for both current and possible future task demands at once., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Berners-Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Odors guide food seeking, and food intake modulates olfactory function. This interaction is mediated by appetite-regulating hormones like ghrelin, insulin, and leptin, which alter activity in the rodent olfactory bulb, but their effects on downstream olfactory cortices have not yet been established in humans. The olfactory tract connects the olfactory bulb to the cortex through 3 main striae, terminating in the piriform cortex (PirC), amygdala (AMY), olfactory tubercule (OT), and anterior olfactory nucleus (AON). Here, we test the hypothesis that appetite-regulating hormones modulate olfactory processing in the endpoints of the olfactory tract and the hypothalamus. We collected odor-evoked functional magnetic resonance imaging (fMRI) responses and plasma levels of ghrelin, insulin, and leptin from human subjects (n = 25) after a standardized meal. We found that a hormonal composite measure, capturing variance relating positively to insulin and negatively to ghrelin, correlated inversely with odor intensity ratings and fMRI responses to odorized vs. clean air in the hypothalamus, OT, and AON. No significant correlations were found with activity in PirC or AMY, the endpoints of the lateral stria. Exploratory whole-brain analyses revealed significant correlations near the diagonal band of Broca and parahippocampal gyrus. These results demonstrate that high (low) blood plasma concentrations of insulin (ghrelin) decrease perceived odor intensity and odor-evoked activity in the cortical targets of the medial and intermediate striae of the olfactory tract, as well as the hypothalamus. These findings expand our understanding of the cortical mechanisms by which metabolic hormones in humans modulate olfactory processing after a meal., (Published by Oxford University Press on behalf of US Government 2023.)

It is well known that the state of hunger can modulate hormones and hypothalamic neural circuits to drive food-seeking behavior and consumption. However, the role the sensory cortex plays in regulating foraging is much less explored. Here, we investigated whether acute fasting in mice can alter an odor-guided foraging behavior and how it can alter neurons and synapses in the (olfactory) piriform cortex (PC). Acute hunger enhances the motivation of a mouse to search for food pellets and increases food intake. The foraging behavior strongly activates the PC, as revealed by c-Fos immunostaining. The activation of PC is accompanied by an increase in excitation-inhibition ratio of synaptic density. Fasting also enhances the phosphorylation of AMP kinase, a biochemical energy regulator. Taken together, our results uncover a new regulatory brain region and implicate the PC in controlling foraging behavior.

γ-oscillatory activity is ubiquitous across brain areas. Numerous studies have suggested that γ-synchrony is likely to enhance the transmission of sensory information. However, direct causal evidence is still lacking. Here, we test this hypothesis in the mouse olfactory system, where local GABAergic granule cells (GCs) in the olfactory bulb shape mitral/tufted cell (MTC) excitatory output from the olfactory bulb. By optogenetically modulating GC activity, we successfully dissociate MTC γ-synchronization from its firing rates. Recording of odor responses in downstream piriform cortex neurons shows that increasing MTC γ-synchronization enhances cortical neuron odor-evoked firing rates, reduces response variability, and improves odor ensemble representation. These gains occur despite a reduction in MTC firing rates. Furthermore, reducing MTC γ-synchronization without changing the MTC firing rates, by suppressing GC activity, degrades piriform cortex odor-evoked responses. These findings provide causal evidence that increased γ-synchronization enhances the transmission of sensory information between two brain regions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Animals recognize groups and mixtures of odors as a unitary object. This ability is crucial to generalize known odors to newly encountered ones despite variations. However, it remains largely unknown how multitudes of odors are represented and organized in the higher brain regions to support odor object recognition. Here we discuss recent advances uncovering the population odor responses in the rodent piriform cortex and the Drosophila mushroom body, and highlight the emerging principles on the organization, mechanism, stereotypy, and experience-dependence of central odor representations., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In chemical sensation, multiple models have been proposed to explain how odors are represented in the olfactory cortex. One hypothesis is that the combinatorial identity of active neurons within sniff-related time windows is critical, whereas another model proposes that it is the temporal structure of neural activity that is essential for encoding odor information. We find that top-down feedback to the main olfactory bulb dictates the information transmitted to the piriform cortex and switches between these coding strategies. Using a detailed network model, we demonstrate that feedback control of inhibition influences the excitation-inhibition balance in mitral cells, restructuring the dynamics of piriform cortical cells. This results in performance improvement in odor discrimination tasks. These findings present a framework for early olfactory computation, where top-down feedback to the bulb flexibly shapes the temporal structure of neural activity in the piriform cortex, allowing the early olfactory system to dynamically switch between two distinct coding models., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Feedforward inhibitory circuits are key contributors to the complex interplay between excitation and inhibition in the brain. Little is known about the function of feedforward inhibition in the primary olfactory (piriform) cortex. Using in vivo two-photon-targeted patch clamping and calcium imaging in mice, we find that odors evoke strong excitation in two classes of interneurons - neurogliaform (NG) cells and horizontal (HZ) cells - that provide feedforward inhibition in layer 1 of the piriform cortex. NG cells fire much earlier than HZ cells following odor onset, a difference that can be attributed to the faster odor-driven excitatory synaptic drive that NG cells receive from the olfactory bulb. As a result, NG cells strongly but transiently inhibit odor-evoked excitation in layer 2 principal cells, whereas HZ cells provide more diffuse and prolonged feedforward inhibition. Our findings reveal unexpected complexity in the operation of inhibition in the piriform cortex., Competing Interests: NS, MT, KA, HH, JB No competing interests declared, (© 2022, Suzuki et al.)

The olfactory bulb (OB) delivers sensory information to the piriform cortex (PC) and other components of the olfactory system. OB-PC synapses have been reported to express short-lasting forms of synaptic plasticity, whereas long-term potentiation (LTP) of the anterior PC (aPC) occurs predominantly by activating inputs from the prefrontal cortex. This suggests that brain regions outside the olfactory system may contribute to olfactory information processing and storage. Here, we compared functional magnetic resonance imaging BOLD responses triggered during 20 or 100 Hz stimulation of the OB. We detected BOLD signal increases in the anterior olfactory nucleus (AON), PC and entorhinal cortex, nucleus accumbens, dorsal striatum, ventral diagonal band of Broca, prelimbic-infralimbic cortex (PrL-IL), dorsal medial prefrontal cortex, and basolateral amygdala. Significantly stronger BOLD responses occurred in the PrL-IL, PC, and AON during 100 Hz compared with 20 Hz OB stimulation. LTP in the aPC was concomitantly induced by 100 Hz stimulation. Furthermore, 100 Hz stimulation triggered significant nuclear immediate early gene expression in aPC, AON, and PrL-IL. The involvement of the PrL-IL in this process is consistent with its putative involvement in modulating behavioral responses to odor experience. Furthermore, these results indicate that OB-mediated information storage by the aPC is embedded in a connectome that supports valence evaluation., (© The Author(s) 2021. Published by Oxford University Press.)

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli., Competing Interests: The authors declare no completing interest.

The brain forms robust associations between odors and emotionally salient memories, making odors especially effective at triggering fearful or traumatic memories. Using Pavlovian olfactory fear conditioning (OFC), a variant of the traditional tone-shock paradigm, this study explored the changes involved in its processing. We assessed the expression of neuronal plasticity markers phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB) and phosphorylated mitogen-activated protein kinase (pMAPK) 24 h and 14 days following OFC, in newborn neurons (EdU+) and in brain regions associated with olfactory memory processing; the olfactory bulb, piriform cortex, amygdale, and hippocampus. Here, we show that all proliferating neurons in the dentate gyrus of the hippocampus and glomerular layer of the olfactory bulb were colocalized with pCREB at 24 h and 14 days post-conditioning, and the number of proliferating neurons at both time points were statistically similar. This suggests the occurrence of long-term potentiation within the neurons of this pathway. Finally, OFC significantly increased the density of pCREB- and pMAPK-positive immunoreactive neurons in the medial and cortical subnuclei of the amygdala and the posterior piriform cortex, suggesting their key involvement in its processing. Together, our investigation identifies changes in neuroplasticity within critical neural circuits responsible for olfactory fear memory., (© The Author(s) 2022. Published by Oxford University Press.)

Odours are a fundamental part of the sensory environment used by animals to guide behaviours such as foraging and navigation 1,2 . Primary olfactory (piriform) cortex is thought to be the main cortical region for encoding odour identity 3-8 . Here, using neural ensemble recordings in freely moving rats performing an odour-cued spatial choice task, we show that posterior piriform cortex neurons carry a robust spatial representation of the environment. Piriform spatial representations have features of a learned cognitive map, being most prominent near odour ports, stable across behavioural contexts and independent of olfactory drive or reward availability. The accuracy of spatial information carried by individual piriform neurons was predicted by the strength of their functional coupling to the hippocampal theta rhythm. Ensembles of piriform neurons concurrently represented odour identity as well as spatial locations of animals, forming an odour-place map. Our results reveal a function for piriform cortex in spatial cognition and suggest that it is well-suited to form odour-place associations and guide olfactory-cued spatial navigation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

In the hippocampus, the contributions of N-methyl-D-aspartate receptors (NMDARs) and L-type calcium channels (LTCCs) to neuronal transmission and synaptic plasticity change with aging, underlying calcium dysregulation and cognitive dysfunction. However, the relative contributions of NMDARs and LTCCs in other learning encoding structures during aging are not known. The piriform cortex (PC) plays a significant role in odor associative memories, and like the hippocampus, exhibits forms of long-term synaptic plasticity. Here, we investigated the expression and contribution of NMDARs and LTCCs in long-term depression (LTD) of the PC associational fiber pathway in three cohorts of Sprague Dawley rats: neonatal (1-2 weeks), young adult (2-3 months) and aged (20-25 months). Using a combination of slice electrophysiology, Western blotting, fluorescent immunohistochemistry and confocal imaging, we observed a shift from an NMDAR to LTCC mediation of LTD in aged rats, despite no difference in the amount of LTD expression. These changes in plasticity are related to age-dependent differential receptor expression in the PC. LTCC Cav1.2 expression relative to postsynaptic density protein 95 is increased in the associational pathway of the aged PC layer Ib. Enhanced LTCC contribution in synaptic depression in the PC may contribute to altered olfactory function and learning with aging.

Neural oscillations can couple networks of brain regions, especially at lower frequencies. The nasal respiratory rhythm, which elicits robust olfactory bulb oscillations, has been linked to episodic memory, locomotion, and exploration, along with widespread oscillatory coherence. The piriform cortex is implicated in propagating the olfactory-bulb-driven respiratory rhythm, but this has not been tested explicitly in the context of both hippocampal theta and nasal respiratory rhythm during exploratory behaviors. We investigated systemwide interactions during foraging behavior, which engages respiratory and theta rhythms. Local field potentials from the olfactory bulb, piriform cortex, dentate gyrus, and CA1 of hippocampus, primary visual cortex, and nasal respiration were recorded simultaneously from male rats. We compared interactions among these areas while rats foraged using either visual or olfactory spatial cues. We found high coherence during foraging compared with home cage activity in two frequency bands that matched slow and fast respiratory rates. Piriform cortex and hippocampus maintained strong coupling at theta frequency during periods of slow respiration, whereas other pairs showed coupling only at the fast respiratory frequency. Directional analysis shows that the modality of spatial cues was matched to larger influences in the network by the respective primary sensory area. Respiratory and theta rhythms also coupled to faster oscillations in primary sensory and hippocampal areas. These data provide the first evidence of widespread interactions among nasal respiration, olfactory bulb, piriform cortex, and hippocampus in awake freely moving rats, and support the piriform cortex as an integrator of respiratory and theta activity. SIGNIFICANCE STATEMENT Recent studies have shown widespread interactions between the nasally driven respiratory rhythm and neural oscillations in hippocampus and neocortex. With this study, we address how the respiratory rhythm interacts with ongoing slow brain rhythms across olfactory, hippocampal, and visual systems in freely moving rats. Patterns of network connectivity change with behavioral state, with stronger interactions at fast and slow respiratory frequencies during foraging as compared with home cage activity. Routing of interactions between sensory cortices depends on the modality of spatial cues present during foraging. Functional connectivity and cross-frequency coupling analyses suggest strong bidirectional interactions between olfactory and hippocampal systems related to respiration and point to the piriform cortex as a key area for mediating respiratory and theta rhythms., (Copyright © 2021 the authors.)

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., (© 2021. The Author(s).)

The piriform cortex (PCx) is essential for learning of odor information. The current view postulates that odor learning in the PCx is mainly due to plasticity in intracortical (IC) synapses, while odor information from the olfactory bulb carried via the lateral olfactory tract (LOT) is 'hardwired.' Here, we revisit this notion by studying location- and pathway-dependent plasticity rules. We find that in contrast to the prevailing view, synaptic and optogenetically activated LOT synapses undergo strong and robust long-term potentiation (LTP) mediated by only a few local NMDA-spikes delivered at theta frequency, while global spike timing-dependent plasticity (STDP) protocols failed to induce LTP in these distal synapses. In contrast, IC synapses in apical and basal dendrites undergo plasticity with both NMDA-spikes and STDP protocols but to a smaller extent compared with LOT synapses. These results are consistent with a self-potentiating mechanism of odor information via NMDA-spikes that can form branch-specific memory traces of odors that can further associate with contextual IC information via STDP mechanisms to provide cognitive and emotional value to odors., Competing Interests: AK, EB, JS No competing interests declared, (© 2021, Kumar et al.)

Encoding and retaining novel sequences of sensory stimuli in working memory is crucial for adaptive behavior. A fundamental challenge for the central nervous system is to maintain each sequence item in an active and discriminable state, while also preserving their temporal context. Nested neural oscillations have been postulated to disambiguate the "what" and "when" of sequences, but the mechanisms by which these multiple streams of information are coordinated in the human brain remain unclear. Drawing from foundational animal studies, we recorded local field potentials from the human piriform cortex and hippocampus during a working memory task in which subjects experienced sequences of three distinct odors. Our data revealed a unique organization of odor memories across multiple timescales of the theta rhythm. During encoding, odors elicited greater gamma at distinct theta phases in both regions, time stamping their positions in the sequence, whereby the robustness of this effect was predictive of temporal order memory. During maintenance, stimulus-driven patterns of theta-coupled gamma were spontaneously reinstated in piriform cortex, recapitulating the order of the initial sequence. Replay events were time compressed across contiguous theta cycles, coinciding with periods of enhanced piriform-hippocampal theta-phase synchrony, and their prevalence forecasted subsequent recall accuracy on a trial-by-trial basis. Our data provide a novel link between endogenous replay orchestrated by the theta rhythm and short-term retention of sequential memories in the human brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neuronal oscillations route external and internal information across brain regions. In the olfactory system, the two central nodes-the olfactory bulb (OB) and the piriform cortex (PC)-communicate with each other via neural oscillations to shape the olfactory percept. Communication between these nodes have been well characterized in non-human animals but less is known about their role in the human olfactory system. Using a recently developed and validated EEG-based method to extract signals from the OB and PC sources, we show in healthy human participants that there is a bottom-up information flow from the OB to the PC in the beta and gamma frequency bands, while top-down information from the PC to the OB is facilitated by delta and theta oscillations. Importantly, we demonstrate that there was enough information to decipher odor identity above chance from the low gamma in the OB-PC oscillatory circuit as early as 100 ms after odor onset. These data further our understanding of the critical role of bidirectional information flow in human sensory systems to produce perception. However, future studies are needed to determine what specific odor information is extracted and communicated in the information exchange., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Olfaction could prove to be an early marker of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. To use olfaction for disease diagnosis, elucidating the standard olfactory functions in healthy humans is necessary. However, the olfactory function in the human brain is less frequently assessed because of methodological difficulties associated with olfactory-related cerebral areas. Using ultra-high fields (UHF), functional magnetic resonance imaging (fMRI) with high spatial resolution and sensitivity may allow for the measurement of activation in the cerebral areas. This study aimed to apply 7-Tesla fMRI to assess olfactory function in the human brain by exposing individuals to four different odorants for 8 s. We found that olfactory stimulation mainly activated the piriform and orbitofrontal cortex in addition to the amygdala. Among these regions, univariate fMRI analysis indicated that subjective odor intensity significantly correlated with the averaged fMRI signals in the piriform cortex but not with subjective hedonic tone in any region. In contrast, multivariate fMRI analysis showed that subjective hedonic tone could be discriminated from the fMRI response patterns in the posterior orbitofrontal cortex. Thus, the piriform cortex is mainly associated with subjective odor intensity, whereas the posterior orbitofrontal cortex are involved in the discrimination of the subjective hedonic tone of the odorant. UHF-fMRI may be useful for assessing olfactory function in the human brain., Competing Interests: Declaration of Competing Interest YD is employed by Daikin Industries, Ltd. UC, HB, and IK have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

The piriform cortex is rich in recurrent excitatory synaptic connections between pyramidal neurons. We asked how such connections could shape cortical responses to olfactory lateral olfactory tract (LOT) inputs. For this, we constructed a computational network model of anterior piriform cortex with 2000 multicompartment, multiconductance neurons (500 semilunar, 1000 layer 2 and 500 layer 3 pyramids; 200 superficial interneurons of two types; 500 deep interneurons of three types; 500 LOT afferents), incorporating published and unpublished data. With a given distribution of LOT firing patterns, and increasing the strength of recurrent excitation, a small number of firing patterns were observed in pyramidal cell networks: first, sparse firings; then temporally and spatially concentrated epochs of action potentials, wherein each neuron fires one or two spikes; then more synchronized events, associated with bursts of action potentials in some pyramidal neurons. We suggest that one function of anterior piriform cortex is to transform ongoing streams of input spikes into temporally focused spike patterns, called here "cell assemblies", that are salient for downstream projection areas., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Immature neurons are maintained in cortical regions of the adult mammalian brain. In rodents, many of these immature neurons can be identified in the piriform cortex based on their high expression of early neuronal markers, such as doublecortin (DCX) and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule plays critical roles in different neurodevelopmental events. Taking advantage of a DCX-CreERT2/Flox-EGFP reporter mice, we investigated the impact of targeted PSA enzymatic depletion in the piriform cortex on the fate of immature neurons. We report here that the removal of PSA accelerated the final development of immature neurons. This was revealed by a higher frequency of NeuN expression, an increase in the number of cells carrying an axon initial segment (AIS), and an increase in the number of dendrites and dendritic spines on the immature neurons. Taken together, our results demonstrated the crucial role of the PSA moiety in the protracted development of immature neurons residing outside of the neurogenic niches. More studies will be required to understand the intrinsic and extrinsic factors affecting PSA-NCAM expression to understand how the brain regulates the incorporation of these immature neurons to the established neuronal circuits of the adult brain.

The piriform cortex (PC) is a major cortical processing center for the sense of smell that receives direct inputs from the olfactory bulb. In mice, the PC consists of three neuronal layers, which are populated by cells with distinct developmental origins. One origin of PC neurons is the pool of Dbx1-expressing neural progenitors located in the ventral pallium at the pallial-subpallial boundary. Since the precise mechanisms of PC neuron development are largely unknown, we sought to define the distribution, timing of neurogenesis, morphology and projection patterns of PC neurons from the Dbx1 lineage. We found that Dbx1-lineage neurons are preferentially distributed in layer 2 and enriched in the ventral portion of the PC. Further, Dbx1 neurons are early-born neurons and contribute to most neuronal subtypes in the PC. Our data also revealed an enrichment of Dbx1-lineage neurons in the ventral anterior PC that project to the orbitofrontal cortex. These findings suggest a specific association between the developmental origin of PC neurons and their neuronal properties.

An important measure in pain research is the intensity of nociceptive stimuli and their cortical representation. However, there is evidence of different cerebral representations of nociceptive stimuli, including the fact that cortical areas recruited during processing of intranasal nociceptive chemical stimuli included those outside the traditional trigeminal areas. Therefore, the aim of this study was to investigate the major cerebral representations of stimulus intensity associated with intranasal chemical trigeminal stimulation. Trigeminal stimulation was achieved with carbon dioxide presented to the nasal mucosa. Using a single-blinded, randomized crossover design, 24 subjects received nociceptive stimuli with two different stimulation paradigms, depending on the just noticeable differences in the stimulus strengths applied. Stimulus-related brain activations were recorded using functional magnetic resonance imaging with event-related design. Brain activations increased significantly with increasing stimulus intensity, with the largest cluster at the right Rolandic operculum and a global maximum in a smaller cluster at the left lower frontal orbital lobe. Region of interest analyses additionally supported an activation pattern correlated with the stimulus intensity at the piriform cortex as an area of special interest with the trigeminal input. The results support the piriform cortex, in addition to the secondary somatosensory cortex, as a major area of interest for stimulus strength-related brain activation in pain models using trigeminal stimuli. This makes both areas a primary objective to be observed in human experimental pain settings where trigeminal input is used to study effects of analgesics., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Odors activate distributed ensembles of neurons within the piriform cortex, forming cortical representations of odor thought to be essential to olfactory learning and behaviors. This odor response is driven by direct input from the olfactory bulb, but is also shaped by a dense network of associative or intracortical inputs to piriform, which may enhance or constrain the cortical odor representation. With optogenetic techniques, it is possible to functionally isolate defined inputs to piriform cortex and assess their potential to activate or inhibit piriform pyramidal neurons. The anterior olfactory nucleus (AON) receives direct input from the olfactory bulb and sends an associative projection to piriform cortex that has potential roles in the state-dependent processing of olfactory behaviors. Here, we provide a detailed functional assessment of the AON afferents to piriform in male and female C57Bl/6J mice. We confirm that the AON forms glutamatergic excitatory synapses onto piriform pyramidal neurons; and while these inputs are not as strong as piriform recurrent collaterals, they are less constrained by disynaptic inhibition. Moreover, AON-to-piriform synapses contain a substantial NMDAR-mediated current that prolongs the synaptic response at depolarized potentials. These properties of limited inhibition and slow NMDAR-mediated currents result in strong temporal summation of AON inputs within piriform pyramidal neurons, and suggest that the AON could powerfully enhance activation of piriform neurons in response to odor. SIGNIFICANCE STATEMENT Odor information is transmitted from olfactory receptors to olfactory bulb, and then to piriform cortex, where ensembles of activated neurons form neural representations of the odor. While these ensembles are driven by primary bulbar afferents, and shaped by intracortical recurrent connections, the potential for another early olfactory area, the anterior olfactory nucleus (AON), to contribute to piriform activity is not known. Here, we use optogenetic circuit-mapping methods to demonstrate that AON inputs can significantly activate piriform neurons, as they are coupled to NMDAR currents and to relatively modest disynaptic inhibition. The AON may enhance the piriform odor response, encouraging further study to determine the states or behaviors through which AON potentiates the cortical response to odor., (Copyright © 2020 the authors.)

During the first ten postnatal days (P), infant rodents can learn olfactory preferences for novel odors if they are paired with thermo-tactile stimuli that mimic components of maternal care. After P10, the thermo-tactile pairing becomes ineffective for conditioning. The current explanation for this change in associative learning is the alteration in the norepinephrine (NE) inputs from the locus coeruleus (LC) to the olfactory bulb (OB) and the anterior piriform cortex (aPC). By combining patch-clamp electrophysiology and computational simulations, we showed in a recent work that a transitory high responsiveness of the OB-aPC circuit to the maternal odor is an alternative mechanism that could also explain early olfactory preference learning and its cessation after P10. That result relied solely on the maturational properties of the aPC pyramidal cells. However, the GABAergic system undergoes important changes during the same period. To address the importance of the maturation of the GABAergic system for early olfactory learning, we incorporated data from the GABA inputs, obtained from in vitro patch-clamp experiment in the aPC of rat pups aged P5-P7 reported here, to the model proposed in our previous publication. In the younger than P10 OB-aPC circuit with GABA synaptic input, the number of responsive aPC pyramidal cells to the conditioned maternal odor was amplified in 30% compared to the circuit without GABAergic input. When compared with the circuit with other younger than P10 OB-aPC circuit with adult GABAergic input profile, this amplification was 88%. Together, our results suggest that during the olfactory preference learning in younger than P10, the GABAergic synaptic input presumably acts by depolarizing the aPC pyramidal neurons in such a way that it leads to the amplification of the pyramidal neurons response to the conditioned maternal odor. Furthermore, our results suggest that during this developmental period, the aPC pyramidal cells themselves seem to resolve the apparent lack of GABAergic synaptic inhibition by a strong firing adaptation in response to increased depolarizing inputs., (© 2020 Oruro et al.; Published by Cold Spring Harbor Laboratory Press.)

The representation of odor in olfactory cortex (piriform) is distributive and unstructured and can only be afforded behavioral significance upon learning. We performed 2-photon imaging to examine the representation of odors in piriform and in two downstream areas, the orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC), as mice learned olfactory associations. In piriform, we observed that odor responses were largely unchanged during learning. In OFC, 30% of the neurons acquired robust responses to conditioned stimuli (CS+) after learning, and these responses were gated by internal state and task context. Moreover, direct projections from piriform to OFC can be entrained to elicit learned olfactory behavior. CS+ responses in OFC diminished with continued training, whereas persistent representations of both CS+ and CS- odors emerged in mPFC. Optogenetic silencing indicates that these two brain structures function sequentially to consolidate the learning of appetitive associations., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pattern completion, or the ability to retrieve stable neural activity patterns from noisy or partial cues, is a fundamental feature of memory. Theoretical studies indicate that recurrently connected auto-associative or discrete attractor networks can perform this process. Although pattern completion and attractor dynamics have been observed in various recurrent neural circuits, the role recurrent circuitry plays in implementing these processes remains unclear. In recordings from head-fixed mice, we found that odor responses in olfactory bulb degrade under ketamine/xylazine anesthesia while responses immediately downstream, in piriform cortex, remain robust. Recurrent connections are required to stabilize cortical odor representations across states. Moreover, piriform odor representations exhibit attractor dynamics, both within and across trials, and these are also abolished when recurrent circuitry is eliminated. Here, we present converging evidence that recurrently-connected piriform populations stabilize sensory representations in response to degraded inputs, consistent with an auto-associative function for piriform cortex supported by recurrent circuitry., Competing Interests: KB, SN, BH, FW, KF No competing interests declared, (© 2020, Bolding et al.)

After the integrative storage of associated signals, a signal induces the recollection of its associated signal, or the other way around. This associative memory is essential to associative thinking, logical reasoning, imagination and computation. In terms of cellular mechanisms underlying associative memory, new mutual synapse innervations are formed among those coactivated neurons, so that they are recruited to be associative memory cells or associative memory neurons. These associative memory cells receive new synapse innervations alongside innate synapse inputs and encode signals carried by these inputs. We proposed to examine microRNAs as initiative factors for recruiting new synapse innervations and associative memory cells. In a mouse model of associative memory characterized as the reciprocal retrieval of associated whisker and odor signals, barrel and piriform cortical neurons gain their ability to encode whisker and odorant signals based on the newly formed synapse innervations between these coactivated cortices besides innate synapse inputs. miRNA-324 and miRNA-133a are required for recruiting these new synapse innervations and associative memory cells as well as sufficient for facilitating their recruitments, but not for innate synapse inputs. Therefore, the coactivation of sensory cortices through microRNA as initiative factor to recruit new mutual synapse innervations and associative memory cells for associative memory., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex., Competing Interests: The authors have declared that no competing interests exist.

The extent of functional maturation and integration of nonproliferative neuronal precursors, becoming neurons in the adult murine piriform cortex, is largely unexplored. We thus questioned whether precursors eventually become equivalent to neighboring principal neurons or whether they represent a novel functional network element. Adult brain neuronal precursors and immature neurons (complex cells) were labeled in transgenic mice (DCX-DsRed and DCX-CreERT2 /flox-EGFP), and their cell fate was characterized with patch clamp experiments and morphometric analysis of axon initial segments. Young (DCX+) complex cells in the piriform cortex of 2- to 4-month-old mice received sparse synaptic input and fired action potentials at low maximal frequency, resembling neonatal principal neurons. Following maturation, the synaptic input detected on older (DCX-) complex cells was larger, but predominantly GABAergic, despite evidence of glutamatergic synaptic contacts. Furthermore, the rheobase current of old complex cells was larger and the maximal firing frequency was lower than those measured in neighboring age-matched principal neurons. The striking differences between principal neurons and complex cells suggest that the latter are a novel type of neuron and new coding element in the adult brain rather than simple addition or replacement for preexisting network components., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Deep brain stimulation (DBS) may help control seizures in individuals with medically intractable epilepsy who are not candidates for resective surgery. The current review focuses on some preclinical studies of DBS of the piriform cortex (PC), an area involved in the generation and maintenance of seizures, as a potential therapeutic option for refractory epilepsy. We also present findings suggesting the safety of low frequency stimulation (LFS) of the PC on memory. A variety of LFS parameters have been suggested as an effective treatment strategy for refractory epilepsy. In generalized epilepsy, however, recent studies suggest that LFS may exacerbate seizures and high frequency stimulation (HFS) might be an alternative. Hence, further studies are required to explore the potential therapeutic targets and proper stimulation parameters for the successful translation of DBS of the PC to the clinic., Competing Interests: Disclosure of conflicts of interest This work was supported by the George Washington University and pilot grant from Clinical and Translational Science Institute at Children's National for Mohamad Z. Koubeissi. There are no other conflicts of interest related to this work. The remaining authors have no conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Most odors are not composed of a single volatile chemical species, but rather are mixtures of many different volatile molecules, the perception of which is dependent on the identity and relative concentrations of the components. Changing either the identity or ratio of components can lead to shifts between configural and elemental perception of the mixture. For example, a 30/70 ratio of ethyl isobutyrate (odorant A, a strawberry scent) and ethyl maltol (odorant B, a caramel scent) is perceived as pineapple by humans - a configural percept distinct from the components. In contrast, a 68/32 ratio of the same odorants is perceived elementally, and is identified as the component odors. Here, we examined single-unit responses in the anterior and posterior piriform cortex (aPCX and pPCX) of mice to these A and B mixtures. We first demonstrate that mouse behavior is consistent with a configural/elemental perceptual shift as concentration ratio varies. We then compared responses to the configural mixture to those evoked by the elemental mixture, as well as to the individual components. Hierarchical cluster analyses suggest that in the mouse aPCX, the configural mixture was coded as distinct from both components, while the elemental mixture was coded as similar to the components. In contrast, mixture perception did not predict pPCX ensemble coding. Similar electrophysiological results were also observed in rats. The results suggest similar perceptual characteristics of the AB mixture across species, and a division in the roles of aPCX and pPCX in the coding of configural and elemental odor mixtures., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The piriform cortex (PC) is a key brain area involved in both processing and coding of olfactory information. It is implicated in various brain disorders, such as epilepsy, Alzheimer's disease, and autism. The PC consists of the anterior (APC) and posterior (PPC) parts, which are different anatomically and functionally. However, the direct input networks to specific neuronal populations within the APC and PPC remain poorly understood. Here, we mapped the whole-brain direct inputs to the two major neuronal populations, the excitatory glutamatergic principal neurons and inhibitory γ-aminobutyric acid (GABA)-ergic interneurons within the APC and PPC using the rabies virus (RV)-mediated retrograde trans-synaptic tracing system. We found that for both types of neurons, APC and PPC share some similarities in input networks, with dominant inputs originating from the olfactory region (OLF), followed by the cortical subplate (CTXsp), isocortex, cerebral nuclei (CNU), hippocampal formation (HPF) and interbrain (IB), whereas the midbrain (MB) and hindbrain (HB) were rarely labeled. However, APC and PPC also show distinct features in their input distribution patterns. For both types of neurons, the input proportion from the OLF to the APC was higher than that to the PPC; while the PPC received higher proportions of inputs from the HPF and CNU than the APC did. Overall, our results revealed the direct input networks of both excitatory and inhibitory neuronal populations of different PC subareas, providing a structural basis to analyze the diverse PC functions., (Copyright © 2020 Wang, Zhang, Chen, Manyande, Haddad, Liu and Xu.)

The hippocampus utilizes olfactospatial information to encode sensory experience by means of synaptic plasticity. Odor exposure is also a potent impetus for hippocampus-dependent memory retrieval. Here, we explored to what extent the piriform cortex directly impacts upon hippocampal information processing and storage. In behaving rats, test-pulse stimulation of the anterior piriform cortex (aPC) evoked field potentials in the dentate gyrus (DG). Patterned stimulation of the aPC triggered both long-term potentiation (LTP > 24 h) and short-term depression (STD), in a frequency-dependent manner. Dual stimulation of the aPC and perforant path demonstrated subordination of the aPC response, which was nonetheless completely distinct in profile to perforant path-induced DG plasticity. Correspondingly, patterned aPC stimulation resulted in somatic immediate early gene expression in the DG that did not overlap with responses elicited by perforant path stimulation. Our results support that the piriform cortex engages in specific control of hippocampal information processing and encoding. This process may underlie the unique role of olfactory cues in information encoding and retrieval of hippocampus-dependent associative memories., (© The Author(s) 2019. Published by Oxford University Press.)

The olfactory bulbs (OBs) are the first site of odor representation in the mammalian brain, and their unique ultrastructure is considered a necessary substrate for spatiotemporal coding of smell. Given this, we were struck by the serendipitous observation at MRI of two otherwise healthy young left-handed women, yet with no apparent OBs. Standardized tests revealed normal odor awareness, detection, discrimination, identification, and representation. Functional MRI of these women's brains revealed that odorant-induced activity in piriform cortex, the primary OB target, was similar in its extent to that of intact controls. Finally, review of a public brain-MRI database with 1,113 participants (606 women) also tested for olfactory performance, uncovered olfaction without anatomically defined OBs in ∼0.6% of women and ∼4.25% of left-handed women. Thus, humans can perform the basic facets of olfaction without canonical OBs, implying extreme plasticity in the functional neuroanatomy of this sensory system., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies have shown that neonate rodents exhibit high ability to learn a preference for novel odors associated with thermo-tactile stimuli that mimics maternal care. Artificial odors paired with vigorous strokes in rat pups younger than 10 postnatal days (P), but not older, rapidly induce an orientation-approximation behavior toward the conditioned odor in a two-choice preference test. The olfactory bulb (OB) and the anterior olfactory cortex (aPC), both modulated by norepinephrine (NE), have been identified as part of a neural circuit supporting this transitory olfactory learning. One possible explanation at the neuronal level for why the odor-stroke pairing induces consistent orientation-approximation behavior in P10, is the coincident activation of prior existent neurons in the aPC mediating this behavior. Specifically, odor-stroke conditioning in P10 pups, promoting orientation-approximation behavior in the former but not in the latter. In order to test this hypothesis, we performed in vitro patch-clamp recordings of the aPC pyramidal neurons from rat pups from two age groups (P5-P8 and P14-P17) and built computational models for the OB-aPC neural circuit based on this physiological data. We conditioned the P5-P8 OB-aPC artificial circuit to an odor associated with NE activation (representing the process of maternal odor learning during mother-infant interactions inside the nest) and then evaluated the response of the OB-aPC circuit to the presentation of the conditioned odor. The results show that the number of responsive aPC neurons to the presentation of the conditioned odor in the P14-P17 OB-aPC circuit was lower than in the P5-P8 circuit, suggesting that at P14-P17, the reduced number of responsive neurons to the conditioned (maternal) odor might not be coincident with the responsive neurons for a second conditioned odor., (© 2020 Oruro et al.; Published by Cold Spring Harbor Laboratory Press.)

In awake rodents, the neural representation of olfactory information in the olfactory bulb is largely dependent on brain state and behavioral context. Learning-modified neural plasticity has been observed in mitral/tufted cells, the main output neurons of the olfactory bulb. Here, we propose that the odor information encoded by mitral/tufted cell responses in awake mice is highly dependent on the behavioral task demands. We used fiber photometry to record calcium signals from the mitral/tufted cell population in awake, head-fixed male mice under different task demands. We found that the mitral/tufted cell population showed similar responses to two distinct odors when the odors were presented in the context of a go/go task, in which the mice received a water reward regardless of the identity of the odor presented. However, when the same odors were presented in a go/no-go task, in which one odor was rewarded and the other was not, then the mitral cell population responded very differently to the two odors, characterized by a robust reduction in the response to the nonrewarded odor. Thus, the representation of odors in the mitral/tufted cell population depends on whether the task requires discrimination of the odors. Strikingly, downstream of the olfactory bulb, pyramidal neurons in the posterior piriform cortex also displayed a task-demand-dependent neural representation of odors, but the anterior piriform cortex did not, indicating that these two important higher olfactory centers use different strategies for neural representation. SIGNIFICANCE STATEMENT The most important task of the olfactory system is to generate a precise representation of odor information under different brain states. Whether the representation of odors by neurons in olfactory centers such as the olfactory bulb and the piriform cortex depends on task demands remains elusive. We find that odor representation in the mitral/tufted cells of the olfactory bulb depends on whether the task requires odor discrimination. A similar neural representation is found in the posterior piriform cortex but not the anterior piriform cortex, indicating that these higher olfactory centers use different representational strategies. The task-demand-dependent representational strategy is likely important for facilitating information processing in higher brain centers responsible for decision making and encoding of salience., (Copyright © 2019 the authors.)

After associative learning, a signal induces the recall of its associated signal, or the other way around. This reciprocal retrieval of associated signals is essential for associative thinking and logical reasoning. For the cellular mechanism underlying this associative memory, we hypothesized that the formation of synapse innervations among coactivated sensory cortices and the recruitment of associative memory cells were involved in the integrative storage and reciprocal retrieval of associated signals. Our study indicated that the paired whisker and olfaction stimulations led to an odorant-induced whisker motion and a whisker-induced olfaction response, a reciprocal form of associative memory retrieval. In mice that showed the reciprocal retrieval of associated signals, their barrel and piriform cortical neurons became mutually innervated through their axon projection and new synapse formation. These piriform and barrel cortical neurons gained the ability to encode both whisker and olfaction signals based on synapse innervations from the innate input and the newly formed input. Therefore, the associated activation of sensory cortices by pairing input signals initiates their mutual synapse innervations, and the neurons innervated by new and innate synapses are recruited to be associative memory cells that encode these associated signals. Mutual synapse innervations among sensory cortices to recruit associative memory cells may compose the primary foundation for the integrative storage and reciprocal retrieval of associated signals. Our study also reveals that new synapses onto the neurons enable these neurons to encode memories to new specific signals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Sleep deprivation has marked effects on food intake, shifting food choices toward energy-dense options. Here we test the hypothesis that neural processing in central olfactory circuits, in tandem with the endocannabinoid system (ECS), plays a key role in mediating this relationship. We combined a partial sleep-deprivation protocol, pattern-based olfactory neuroimaging, and ad libitum food intake to test how central olfactory mechanisms alter food intake after sleep deprivation. We found that sleep restriction increased levels of the ECS compound 2-oleoylglycerol (2-OG), enhanced encoding of food odors in piriform cortex, and shifted food choices toward energy-dense food items. Importantly, the relationship between changes in 2-OG and food choices was formally mediated by odor-evoked connectivity between the piriform cortex and insula, a region involved in integrating feeding-related signals. These findings describe a potential neurobiological pathway by which state-dependent changes in the ECS may modulate chemosensory processing to regulate food choices., Competing Interests: SB, JH, RR, PZ, JG No competing interests declared, TK Reviewing editor, eLife, (© 2019, Bhutani et al.)

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 β 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., (Copyright © 2019 Olofsson et al.)

The retrieval of odor-related memories shapes animal behavior. The anterior piriform cortex (aPC) is the largest part of the olfactory cortex, and it plays important roles in olfactory processing and memory. However, it is still unclear whether specific cellular mechanisms in the aPC control olfactory memory, depending on the appetitive or aversive nature of the stimuli involved. Cannabinoid-type 1 (CB1) receptors are present in the aPC (aPC-CB1), but their potential impact on olfactory memory was never explored. Here, we used a combination of behavioral, genetic, anatomical, and electrophysiological approaches to characterize the functions of aPC-CB1 receptors in the regulation of appetitive and aversive olfactory memory. Pharmacological blockade or genetic deletion of aPC-CB1 receptors specifically impaired the retrieval of conditioned odor preference (COP). Interestingly, expression of conditioned odor aversion (COA) was unaffected by local CB1 receptor blockade, indicating that the role of aPC endocannabinoid signaling is selective for retrieval of appetitive memory. Anatomical investigations revealed that CB1 receptors are highly expressed on aPC GABAergic interneurons, and ex vivo electrophysiological recordings showed that their pharmacological activation reduces miniature inhibitory post-synaptic currents (mIPSCs) onto aPC semilunar (SL), but not pyramidal principal neurons. COP retrieval, but not COA, was associated with a specific CB1-receptor-dependent decrease of mIPSCs in SL cells. Altogether, these data indicate that aPC-CB1 receptor-dependent mechanisms physiologically control the retrieval of olfactory memory, depending on odor valence and engaging modulation of local inhibitory transmission., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Identifying shared quantitative features of a neural circuit across species is important for 3 reasons. Often expressed in the form of power laws and called scaling relationships [1, 2], they reveal organizational principles of circuits, make insights gleaned from model systems widely applicable, and explain circuit performance and function, e.g., visual circuits [3, 4]. The visual circuit is topographic [5, 6], wherein retinal neurons target and activate predictable spatial loci in primary visual cortex. The brain, however, contains many circuits, where neuronal targets and activity are unpredictable and distributed throughout the circuit, e.g., olfactory circuits, in which glomeruli (or mitral cells) in the olfactory bulb synapse with neurons distributed throughout the piriform cortex [7-10]. It is unknown whether such circuits, which we term distributed circuits, are scalable. To determine whether distributed circuits scale, we obtained quantitative descriptions of the olfactory bulb and piriform cortex in six mammals using stereology techniques and light microscopy. Two conserved features provide evidence of scalability. First, the number of piriform neurons n and bulb glomeruli g scale as n∼g 3/2 . Second, the average number of synapses between a bulb glomerulus and piriform neuron is invariant at one. Using theory and modeling, we show that these two features preserve the discriminatory ability and precision of odor information across the olfactory circuit. As both abilities depend on circuit size, manipulating size provides evolution with a way to adapt a species to its niche without designing developmental programs de novo. These principles might apply to other distributed circuits like the hippocampus., (Copyright © 2019. Published by Elsevier Ltd.)

Working memory is a critical brain function for maintaining and manipulating information over delay periods of seconds. It is debated whether delay-period neural activity in sensory regions is important for the active maintenance of information during the delay period. Here, we tackle this question by examining the anterior piriform cortex (APC), an olfactory sensory cortex, in head-fixed mice performing several olfactory working memory tasks. Active information maintenance is necessary in these tasks, especially in a dual-task paradigm in which mice are required to perform another distracting task while actively maintaining information during the delay period. Optogenetic suppression of neuronal activity in APC during the delay period impaired performance in all the tasks. Furthermore, electrophysiological recordings revealed that APC neuronal populations encoded odor information in the delay period even with an intervening distracting task. Thus, delay activity in APC is important for active information maintenance in olfactory working memory., Competing Interests: XZ, WY, WW, HF, RH, YC, ZC, CG, SD, AC, CL No competing interests declared, (© 2019, Zhang et al.)

Oscillatory activity is a prominent characteristic of the olfactory system. We previously demonstrated that beta and gamma oscillations occurrence in the olfactory bulb (OB) is modulated by the physical properties of the odorant. However, it remains unknown whether such odor-related modulation of oscillatory patterns is maintained in the piriform cortex (PC) and whether those patterns are similar between the anterior PC (aPC) and posterior PC (pPC). The present study was designed to analyze how different odorant molecular features can affect the local field potential (LFP) oscillatory signals in both the aPC and the pPC in anesthetized rats. As reported in the OB, three oscillatory patterns were observed: standard pattern (gamma + beta), gamma-only and beta-only patterns. These patterns occurred with significantly different probabilities in the two PC areas. We observed that odor identity has a strong influence on the probability of occurrence of LFP beta and gamma oscillatory activity in the aPC. Thus, some odor coding mechanisms observed in the OB are retained in the aPC. By contrast, probability of occurrence of different oscillatory patterns is homogeneous in the pPC with beta-only pattern being the most prevalent one for all the different odor families. Overall, our results confirmed the functional heterogeneity of the PC with its anterior part tightly coupled with the OB and mainly encoding odorant features whereas its posterior part activity is not correlated with odorant features but probably more involved in associative and multi-sensory encoding functions., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

When an animal is facing unfamiliar food, its odor, together with semiochemicals emanating from a conspecific, can constitute a safety message and authorize intake. The piriform cortex (PiC) codes olfactory information, and the inactivation of neurons in the nucleus accumbens (NAc) can acutely trigger consumption. However, the neural circuit and cellular substrate of transition of olfactory perception into value-based actions remain elusive. We detected enhanced activity after social transmission between two mice in neurons of the medial prefrontal cortex (mPFC) that target the NAc and receive projections from the PiC. Exposure to a conspecific potentiated the excitatory postsynaptic currents in NAc projectors, whereas blocking transmission from PiC to mPFC prevented social transmission. Thus, synaptic plasticity in the mPFC is a cellular substrate of social transmission of food safety., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Fear behavior depends on interactions between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), and the expression of fear involves synchronized activity in θ and γ oscillatory activities. In addition, freezing, the most classical measure of fear response in rodents, temporally coincides with the development of sustained 4-Hz oscillations in prefrontal-amygdala circuits. Interestingly, these oscillations were recently shown to depend on the animal's respiratory rhythm, supporting the growing body of evidence pinpointing the influence of nasal breathing on brain rhythms. During fearful states, rats also emit 22-kHz ultrasonic vocalizations (USVs) which drastically affect respiratory rhythm. However, the relationship between 22-kHz USV, respiration, and brain oscillatory activities is still unknown. Yet such information is crucial for a comprehensive understanding of how the different components of fear response collectively modulate rat's brain neural dynamics. Here, we trained male rats in an odor fear conditioning task, while recording simultaneously local field potentials (LFPs) in BLA, mPFC, and olfactory piriform cortex (PIR), together with USV calls and respiration. We show that USV calls coincide with an increase in delta and gamma power and a decrease in theta power. In addition, during USV emission in contrast to silent freezing, there is no coupling between respiratory rate and delta frequency, and the modulation of fast oscillations amplitude relative to the phase of respiration is modified. We propose that sequences of USV calls could result in a differential gating of information within the network of structures sustaining fear behavior, thus potentially modulating fear expression/memory., (Copyright © 2019 Dupin et al.)