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The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on patients with one or more electrode contacts in the piriform cortex. Primary objectives included determining piriform cortex involvement within the electrophysiologically defined epileptogenic network and assessing the effects of electrical stimulation. Twenty-two patients were included in the study. Notably, only one patient exhibited piriform cortex involvement at seizure onset, associated with an olfactory aura. Two patients showed early piriform cortex involvement, while others displayed late or no involvement. Electrical stimulation of the piriform cortex induced after-discharges in three patients and replicated a habitual seizure in one. These findings present a contrast to surgical outcome studies, suggesting that the piriform cortex may not typically play a significant role in the epileptogenic network among patients with non-lesional temporal lobe epilepsy.

Key points Serving as an integral node for cognitive processing and value‐based decision‐making, the orbitofrontal cortex (OFC) plays a multifaceted role in associative learning and reward‐driven behaviours through its widespread synaptic integration with both subcortical structures and sensory cortices. Despite the OFC's robust innervation of the olfactory cortex, the functional implications and underlying mechanisms of this top‐down influence remain largely unexplored. In this study, we demonstrated that the OFC formed both direct excitatory and indirect inhibitory synaptic connections with pyramidal neurons in the anterior piriform cortex (aPC). OFC projection predominantly regulated spontaneous and odour‐evoked excitatory activity in the aPC of awake mice. Importantly, suppression of this OFC–aPC projection disrupted olfactory discrimination learning, potentially due to a consequent decrease in the excitability of aPC principal output neurons following inhibition of this projection. Whole‐cell recordings revealed that olfactory learning increased the intrinsic excitability of aPC neurons while concurrently decreasing OFC input to these neurons. These findings underscore the pivotal influence of orbitofrontal modulation over the olfactory cortex in the context of olfactory learning and provide insight into the associated neurophysiological mechanisms. The orbitofrontal cortex (OFC) densely innervates the anterior piriform cortex (aPC) through direct excitatory synaptic connections. The OFC regulates both spontaneous and odour‐evoked excitatory activities in the aPC of awake mice. Inhibition of OFC projections disrupts olfactory discrimination learning, probably due to reduced excitability of aPC main output neurons. Following olfactory learning, the intrinsic excitability of aPC neurons increases while the OFC–aPC input decreases, highlighting the importance of adaptable OFC input for olfactory learning. These results provide new perspectives on how the OFC's top‐down control modulates sensory integration and associative learning. [ABSTRACT FROM AUTHOR]

Odor information arrives first in the main olfactory bulb and is then broadcasted to the olfactory cortices and striatum. Downstream regions have unique cellular and connectivity architectures that may generate different coding patterns to the same odors. To reveal region-specific response features, tuning and decoding of single-unit populations, we recorded responses to the same odors under the same conditions across regions, namely, the main olfactory bulb (MOB), the anterior olfactory nucleus (AON), the anterior piriform cortex (aPC), and the olfactory tubercle of the ventral striatum (OT), of awake male mice. We focused on chemically closely related aldehydes that still create distinct percepts. The MOB had the highest decoding accuracy for aldehydes and was the only region encoding chemical similarity. The MOB had the highest fraction of inhibited responses and narrowly tuned odor-excited responses in terms of timing and odor selectivity. Downstream, the interconnected AON and aPC differed in their response patterns to the same stimuli. While odor-excited responses dominated the AON, the aPC had a comparably high fraction of odor-inhibited responses. Both cortices share a main output target that is the MOB. This prompted us to test if the two regions convey also different net outputs. Aldehydes activated AON terminals in the MOB as a bulk signal but inhibited those from the aPC. The differential cortical projection responses generalized to complex odors. In summary, olfactory regions reveal specialized features in their encoding with AON and aPC differing in their local computations, thereby generating inverse net centrifugal and intercortical outputs. [ABSTRACT FROM AUTHOR]

Abstract In mammals, NMDA receptor antagonists have been linked to the emergence of high-frequency oscillations (HFO, 130–180 Hz) in cortical and subcortical brain regions. The extent to which transmission of this rhythm is dependent on feedforward (bottom-up) or feedback (top-down) mechanisms is unclear. Previously, we have shown that the olfactory bulb (OB), known to orchestrate oscillations in many brain regions, is an important node in the NMDA receptor-dependent HFO network. Since the piriform cortex (PC) receives major input from the OB, and can modulate OB activity via feedback projections, it represents an ideal site to investigate transmission modalities. Here we show, using silicon probes, that NMDA receptor antagonist HFO are present in the PC associated with current dipoles, although of lower power than the OB. Granger causality and peak-lag analyses implicated the OB as the driver of HFO in the PC. Consistent with this, reversible inhibition of the OB resulted in a reduction of HFO power both locally and in the PC. In contrast, inhibition of the PC had minimal impact on OB activity. Collectively, these findings point to bottom-up mechanisms in mediating the transmission of NMDA receptor antagonist-HFO, at least in olfactory circuits.

Since their clinical application in the 1840s, the greatest mystery surrounding general anesthesia (GA) is how different kinds of general anesthetics cause reversible unconsciousness, and the precise neural mechanisms underlying the processes. Over past years, although many studies revealed the roles of cortex, thalamus, brainstem, especially the sleep-wake circuits in GA-induced loss of consciousness (LOC),the full picture of the neural circuit mechanism of GA is still largely unknown. Recent studies have focused on the importance of other brain regions. Here, we report that the activity of glutamatergic (Glu) neurons in the piriform cortex (PC), a critical brain region for odor encoding, began to increase during the LOC of GA and gradually recovered after recovery of consciousness. Chemical lesions of the anterior PC (APC) neurons accelerated the induction time of isoflurane anesthesia. Chemogenetic and optogenetic activation of APCGlu neurons prolonged isoflurane and sevoflurane anesthesia induction, whereas APCGlu neuron inhibition displayed the opposite effects. Moreover, the modification of APCGlu neurons did not affect the induction or emergence time of propofol GA. In addition, odor processing may be partially involved in the induction of isoflurane and sevoflurane GA regulated by APCGlu neurons. In conclusion, our findings reveal a critical role of APCGlu neurons in inhalational GA induction.

The piriform cortex (PC) occupies both banks of the endorhinal sulcus and has an important role in the pathophysiology of temporal lobe epilepsy (TLE). A recent study showed that resection of more than 50% of PC increased the odds of becoming seizure free by a factor of 16. We report the feasibility of manual segmentation of PC and application of the Geodesic Information Flows (GIF) algorithm to automated segmentation, to guide resection. Manual segmentation of PC was performed by two blinded independent examiners in 60 patients with TLE (55% Left TLE, 52% female) with a median age of 35 years (IQR, 29–47 years) and 20 controls (60% Women) with a median age of 39.5 years (IQR, 31–49). The GIF algorithm was used to create an automated pipeline for parcellating PC which was used to guide excision as part of temporal lobe resection for TLE. Right PC was larger in patients and controls. Parcellation of PC was used to guide anterior temporal lobe resection, with subsequent seizure freedom and no visual field or language deficit. Reliable segmentation of PC is feasible and can be applied prospectively to guide neurosurgical resection that increases the chances of a good outcome from temporal lobe resection for TLE. [ABSTRACT FROM AUTHOR]

Aging is associated with cognitive decline and memory loss in humans. In rats, aging-associated neuronal excitability changes and impairments in learning have been extensively studied in the hippocampus. Here, we investigated the roles of L-type calcium channels (LTCCs) in the rat piriform cortex (PC), in comparison with those of the hippocampus. We employed spatial and olfactory tasks that involve the hippocampus and PC. LTCC blocker nimodipine administration impaired spontaneous location recognition in adult rats (6-9 months). However, the same blocker rescued the spatial learning deficiency in aged rats (19-23 months). In an odor-associative learning task, infusions of nimodipine into either the PC or dorsal CA1 impaired the ability of adult rats to learn a positive odor association. Again, in contrast, nimodipine rescued odor associative learning in aged rats. Aged CA1 neurons had higher somatic expression of LTCC Cav1.2 subunits, exhibited larger afterhyperpolarization (AHP) and lower excitability compared with adult neurons. In contrast, PC neurons from aged rats showed higher excitability and no difference in AHP. Cav1.2 expression was similar in adult and aged PC somata, but relatively higher in PSD95- puncta in aged dendrites. Our data suggest unique features of aging-associated changes in LTCCs in the PC and hippocampus.

The piriform cortex (PC) is part of the olfactory system, principally receiving input from the lateral olfactory tract and projecting to downstream components of the olfactory network, including the amygdala. Based on preclinical studies, PC is vulnerable to injury and can be easily kindled as an onset site for seizures. While the role of PC in human epilepsy has been studied indirectly and the subject of speculation, cases of demonstrated PC seizure onset from direct intracranial recording are rare. We present a pediatric patient with drug-resistant focal reflex epilepsy and right mesial temporal sclerosis with habitual seizures triggered by coconut aroma. The patient underwent stereoelectroencephalography with implantation of olfactory cortices including PC, through which we identified PC seizure onset, mapped high-frequency activity associated with presentation of olfactory stimuli and performance on cognitive tasks, and reproduced habitual seizures via cortical stimulation of PC. Coconut odor did not trigger seizures in our work with the patient. Surgical workup resulted in resection of the patient's right amygdala, PC, and mesial temporal pole, following which she has been seizure free for 20 months without functional decline in cognition or smell. Histological findings from resected tissue showed astrogliosis and subpial gliosis.

Training rodents in a particularly difficult olfactory‐discrimination (OD) task results in the acquisition of the ability to perform the task well, termed 'rule learning'. In addition to enhanced intrinsic excitability and synaptic excitation in piriform cortex pyramidal neurons, rule learning results in increased synaptic inhibition across the whole cortical network to the point where it precisely maintains the balance between inhibition and excitation. The mechanism underlying such precise inhibitory enhancement remains to be explored. Here, we use brain slices from transgenic mice (VGAT‐ChR2‐EYFP), enabling optogenetic stimulation of single GABAergic neurons and recordings of unitary synaptic events in pyramidal neurons. Quantal analysis revealed that learning‐induced enhanced inhibition is mediated by increased quantal size of the evoked inhibitory events. Next, we examined the plasticity of synaptic inhibition induced by long‐lasting, intrinsically evoked spike firing in post‐synaptic neurons. Repetitive depolarizing current pulses from depolarized (−70 mV) or hyperpolarized (−90 mV) membrane potentials induced long‐term depression (LTD) and long‐term potentiation (LTP) of synaptic inhibition, respectively. We found a profound bidirectional increase in the ability to induce both LTD, mediated by L‐type calcium channels, and LTP, mediated by R‐type calcium channels after rule learning. Blocking the GABAB receptor reversed the effect of intrinsic stimulation at −90 mV from LTP to LTD. We suggest that learning greatly enhances the ability to modify the strength of synaptic inhibition of principal neurons in both directions. Such plasticity of synaptic plasticity allows fine‐tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. Key points: Olfactory discrimination rule learning results in long‐lasting enhancement of synaptic inhibition on piriform cortex pyramidal neurons.Quantal analysis of unitary inhibitory synaptic events, evoked by optogenetic minimal stimulation, revealed that enhanced synaptic inhibition is mediated by increased quantal size.Surprisingly, metaplasticity of synaptic inhibition, induced by intrinsically evoked repetitive spike firing, is increased bidirectionally. The susceptibility to both long‐term depression (LTD) and long‐term potentiation (LTP) of inhibition is enhanced after learning.LTD of synaptic inhibition is mediated by L‐type calcium channels and LTP by R‐type calcium channels. LTP is also dependent on activation of GABAB receptors.We suggest that learning‐induced changes in the metaplasticity of synaptic inhibition enable the fine‐tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Cumulative evidence suggests that sensory cortices interact with the basolateral amygdala (BLA) defense circuitry to mediate threat conditioning, memory retrieval, and extinction learning. The olfactory piriform cortex (PC) has been posited as a critical site for olfactory associative memory. Recently, we have shown that N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the PC critically underpins olfactory threat extinction. Aging-associated impairment of olfactory threat extinction is related to the hypofunction of NMDARs in the PC. Methods: In this study, we investigated activation of neuronal cFos and epigenetic marks in the BLA and PC using immunohistochemistry, following olfactory threat conditioning and extinction learning in rats. Results: We found highly correlated cFos activation between the posterior PC (pPC) and BLA. cFos was correlated with the degree of behavioral freezing in the pPC in both adult and aged rats, and in the BLA only in adult rats. Markers of DNA methylation 5 mC and histone acetylation H3K9/K14ac, H3K27ac, and H4ac exhibited distinct training-, region-, and age-dependent patterns of activation. Strong correlations of epigenetic marks between the BLA and pPC in adult rats were found to be a general feature. Conversely, aged rats only exhibited correlations of H3 acetylations between the two structures. Histone acetylation varied as a function of aging, revealed by a reduction of H3K9/K14ac and an increase of H4ac in aged brains at basal condition and following threat conditioning. Discussion: These findings underscore the coordinated role of PC and BLA in olfactory associative memory storage and extinction, with implications for understanding aging related cognitive decline. [ABSTRACT FROM AUTHOR]

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer's dementia (AD) and Parkinson's disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD. [ABSTRACT FROM AUTHOR]

The acquisition of complex rules requires modifications in intrinsic plasticity of excitatory neurons within relevant brain areas. Olfactory discrimination (OD) rule learning occludes slow calcium‐dependent potassium current (sIAHP) in piriform cortex (PC) pyramidal neurons, which increases their intrinsic neuronal excitability. Similar learning‐induced sIAHP changes are demonstrated in hippocampal CA1. The shutdown of sIAHP is mediated by the metabotropic activation of the kainate subtype glutamatergic receptor, GluK2. Here, the duration of training required for OD rule learning increased significantly as the mice matured and aged is first shown, which appears earlier in 5xFAD mice. At the cellular biophysical level, aging is accompanied by reduction in the post‐burst AHP in these neurons, while neuronal excitability remains stable. This is in contrast to aging CA1 neurons that exhibit enhanced post‐burst AHPs in previous reports. Kainate reduces post‐burst AHP in adults, but not in aged PC neurons, whereas it reduces post‐burst AHPs in hippocampal CA1 pyramidal neurons of both young and aged mice. Overexpression of GluK2 in CA1 neurons restores OD learning capabilities in aged wild‐type and 5xFAD mice, to a level comparable to young adults. Activation of GluK2 receptors in selectively vulnerable neurons can prevent aging‐related cognitive decline is suggested. [ABSTRACT FROM AUTHOR]

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.

Extinction of threat memory is a measure of behavioral flexibility. In the absence of additional reinforcement, the extinction of learned behaviors allows animals and humans to adapt to their changing environment. Extinction mechanisms and their therapeutic implications for maladaptive learning have been extensively studied. However, how aging affects extinction learning is much less understood. Using a rat model of olfactory threat extinction, we show that the extinction of olfactory threat memory is impaired in aged Sprague-Darley rats. Following extinction training, long-term depression (LTD) in the piriform cortex (PC) was inducible ex vivo in aged rats and was NMDA receptor (NMDAR)-independent. On the other hand, adult rats acquired successful olfactory threat extinction, and LTD was not inducible following extinction training. Neuronal cFos activation in the posterior PC correlated with learning and extinction performance in rats. NMDAR blockade either systemically or locally in the PC during extinction training prevented successful extinction in adult rats, following which NMDAR-dependent LTD became inducible ex vivo. This suggests that extinction learning employs NMDAR-dependent LTD mechanisms in the PC of adult rats, thus occluding further LTD induction ex vivo. The rescue of olfactory threat extinction in aged rats by D-cycloserine, a partial NMDAR agonist, suggests that the impairment in olfactory threat extinction of aged animals may relate to NMDAR hypofunctioning and a lack of NMDAR-dependent LTD. These findings are consistent with an age-related switch from NMDAR-dependent to NMDAR-independent LTD in the PC. Optimizing NMDAR function in sensory cortices may improve learning and flexible behavior in the aged population. [ABSTRACT FROM AUTHOR]

Olfaction is a critical sense that allows animals to navigate and understand their environment. In mammals, the critical brain structure to receive and process olfactory information is the olfactory bulb, a structure characterized by a laminated pattern with different types of neurons, some of which project to distant telencephalic structures, like the piriform cortex, the amygdala, and the hippocampal formation. Therefore, the olfactory bulb is the first structure of a complex cognitive network that relates olfaction to different types of memory, including episodic memories. The olfactory bulb continuously adds inhibitory newborn neurons throughout life; these cells locate both in the granule and glomerular layers and integrate into the olfactory circuits, inhibiting projection neurons. However, the roles of these cells modulating olfactory memories are unclear, particularly their role in fear memories. We consider that olfactory neurogenesis might modulate olfactory fear memories by a plastic process occurring in the olfactory bulb. [ABSTRACT FROM AUTHOR]

Microscopic neuroanatomy of limbic system and basal forebrain on MRI is complex and is a terra incognita for many radiologists, clinicians, and neuroscientists. Interestingly, most of the important structures/at least anatomical regions containing these structures demonstrable on cadaveric and surgical dissections can be identified on clinical MRI, with 3T being much better than 1.5T. This article teaches the practical MRI identification of these structures which will greatly help in evaluating complex ailments like temporal lobe epilepsy, Alzheimer dementia, and other neuropsychiatric disorders. This knowledge will also aid in accurate reporting of tumor spread along the white matter fasciculi in the temporal stem/basal forebrain region. Limbic system includes the mesial temporal structures and their connections, piriform cortex including "area tempestas," and the septal area comprising of subcallosal area and paraterminal gyrus. Basal forebrain includes structures like substantia innominata with basal nucleus of Meynert, diagonal gyrus/diagonal band of Broca, and nucleus accumbens lying in between the anterior perforated substance inferiorly and the anterior commissure superiorly. [ABSTRACT FROM AUTHOR]

Representational drift is a phenomenon of increasing interest in the cognitive and neural sciences. While investigations are ongoing for other sensory cortices, recent research has demonstrated the pervasiveness in which it occurs in the piriform cortex for olfaction. This gradual weakening and shifting of stimulus‐responsive cells has critical implications for sensory stimulus–response models and perceptual decision‐making. While representational drift may complicate traditional sensory processing models, it could be seen as an advantage in olfaction, as animals live in environments with constantly changing and unpredictable chemical information. Non‐topographical encoding in the olfactory system may aid in contextualizing reactions to promiscuous odor stimuli, facilitating adaptive animal behavior and survival. This article suggests that traditional models of stimulus–(neural) response mapping in olfaction may need to be reevaluated and instead motivates the use of dynamical systems theory as a methodology and conceptual framework. [ABSTRACT FROM AUTHOR]

The olfactory tubercle (OT), which is a component of the olfactory cortex and ventral striatum, has functional domains that play a role in odor-guided motivated behaviors. Learning odor-guided attractive and aversive behavior activates the anteromedial (am) and lateral (l) domains of the OT, respectively. However, the mechanism driving learning-dependent activation of specific OT domains remains unknown. We hypothesized that the neuronal connectivity of OT domains is plastically altered through olfactory experience. To examine the plastic potential of synaptic connections to OT domains, we optogenetically stimulated intracortical inputs from the piriform cortex or sensory inputs from the olfactory bulb to the OT in mice in association with a food reward for attractive learning and electrical foot shock for aversive learning. For both intracortical and sensory connections, axon boutons that terminated in the OT domains were larger in the amOT than in the lOT for mice exhibiting attractive learning and larger in the lOT than in the amOT for mice exhibiting aversive learning. These results indicate that both intracortical and sensory connections to the OT domains have learningdependent plastic potential, suggesting that this plasticity underlies learningdependent activation of specific OT domains and the acquisition of appropriate motivated behaviors. [ABSTRACT FROM AUTHOR]

Introduction: The piriform cortex is one of the large areas of the cerebral cortex that is responsible for actions such as smell, stress and epilepsy. Brain imaging has suggested an important role for the piriform cortex in pain processing. Oxytocin, muscarinic cholinergic and opioid receptors are found in this area of the brain. In this study, following microinjections of oxytocin and antagonists of oxytocin receptors (L-368,889), muscarinic cholinergic receptors (atropine) and opioid receptors (naloxone) in separate and combined treatments into the piriform cortex, their effects on neuropathic pain have been discussed. Methods and Materials: On the first day of the timeline of the study protocol, the neuropathic pain model was created by ligation and then cutting the tibial branch of the sciatic nerve. On the 7th day of the study, guide cannulas were implanted on the right and left side of the piriform cortex. On the 14th day of the study, after microinjection of the tested drugs, mechanical allodynia was recorded using Von Frey filaments. Results: Microinjection of oxytocin (2.5 and 10 ng/site) into the piriform cortex alleviated mechanical allodynia by increasing the 50% paw withdrawal threshold (PWT 50%). Prior microinjection of L-368,899 (20 ng/site), atropine (100 ng/site) and naloxone (100 ng/site) into the piriform cortex inhibited the hypo-sensitivity effect of oxytocin. Conclusion: Referring to the results, it can be said that oxytocin in the piriform cortex directly through oxytocin receptors and also in cooperation with muscarinic cholinergic and opioid receptors is involved in neuropathic pain processing. [ABSTRACT FROM AUTHOR]

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.

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer’s dementia (AD) and Parkinson’s disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD.

Olfaction is a critical sense that allows animals to navigate and understand their environment. In mammals, the critical brain structure to receive and process olfactory information is the olfactory bulb, a structure characterized by a laminated pattern with different types of neurons, some of which project to distant telencephalic structures, like the piriform cortex, the amygdala, and the hippocampal formation. Therefore, the olfactory bulb is the first structure of a complex cognitive network that relates olfaction to different types of memory, including episodic memories. The olfactory bulb continuously adds inhibitory newborn neurons throughout life; these cells locate both in the granule and glomerular layers and integrate into the olfactory circuits, inhibiting projection neurons. However, the roles of these cells modulating olfactory memories are unclear, particularly their role in fear memories. We consider that olfactory neurogenesis might modulate olfactory fear memories by a plastic process occurring in the olfactory bulb.

Introduction: Patients with early-onset Alzheimer's disease (EOAD) experience seizures and subclinical epileptiform activity, which may accelerate cognitive and functional decline. Antiseizure medicines (ASMs) may be a tractable disease-modifying strategy; numerous ASMs are marketed with well-established safety. However, little information is available to guide ASM selection as few studies have rigorously quantified ASM potency and tolerability in traditional seizure models in rodents with EOAD-associated risk factors. Presenilin 2 (PSEN2) variants evoke EOAD, and these patients experience seizures. This study thus established the anticonvulsant profile of mechanistically distinct ASMs in the frontline 6-Hz limbic seizure test evoked in PSEN2-knockout (KO) mice to better inform seizure management in EOAD. Methods: The median effective dose (ED50) of prototype ASMs was quantified in the 6-Hz test in male and female PSEN2-KO and wild-type (WT) C57BL/6J mice (3-4 months old). Minimal motor impairment (MMI) was assessed to estimate a protective index (PI). Immunohistological detection of cFos established the extent to which 6-Hz stimulation activates discrete brain regions in KO vs. WT mice. Results: There were significant genotype-related differences in the potency and tolerability of several ASMs. Valproic acid and levetiracetam were significantly more potent in male KO than in WT mice. Additionally, high doses of valproic acid significantly worsened MMI in KO mice. Conversely, carbamazepine was significantly less potent in female KO vs. WT mice. In both male and female KO mice vs. WTs, perampanel and lamotrigine were equally potent. However, there were marked genotype-related shifts in PI of both carbamazepine and perampanel, with KO mice exhibiting less MMI at the highest doses tested. Gabapentin was ineffective against 6-Hz seizures in KO mice vs. WTs without MMI changes. Neuronal activation 90min following 6-Hz stimulation was significantly increased in the posterior parietal association cortex overlying CA1 and in the piriform cortex of WT mice, while stimulation-induced increases in cFos immunoreactivity were absent in KO mice. Discussion: Acute ASM potency and tolerability in the high-throughput 6-Hz test may be significantly altered with loss of normal PSEN2 function. Seizures in discrete EOAD populations may benefit from precisely selected medicines optimized for primary ASM pharmacological mechanisms. [ABSTRACT FROM AUTHOR]

Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid‐induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. Key points: While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown.In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy.PC pyramidal neurons are hyperexcited during epileptogenesis.Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti‐epileptic effect for both electrical kindling and kainic acid‐induced acute seizures.The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity. [ABSTRACT FROM AUTHOR]

The recent identification of a population of non-newly born, prenatally generated "immature" neurons in the layer II of the piriform cortex (cortical immature neurons, cINs), raises questions concerning their maintenance or depletion through the lifespan. Most forms of brain structural plasticity progressively decline with age, a feature that is particularly prominent in adult neurogenesis, due to stem cell depletion. By contrast, the entire population of the cINs is produced during embryogenesis. Then these cells simply retain immaturity in postnatal and adult stages, until they "awake" to complete their maturation and ultimately integrate into neural circuits. Hence, the question remains open whether the cINs, which are not dependent on stem cell division, might follow a similar pattern of age-related reduction, or in alternative, might leave a reservoir of young, undifferentiated cells in the adult and aging brain. Here, the number and features of cINs were analyzed in the mouse piriform cortex from postnatal to advanced ages, by using immunocytochemistry for the cytoskeletal marker doublecortin. The abundance and stage of maturation of cINs, along with the expression of other markers of maturity/immaturity were investigated. Despite a marked decrease in this neuronal population during juvenile stages, reminiscent of that observed in hippocampal neurogenesis, a small amount of highly immature cINs persisted up to advanced ages. Overall, albeit reducing in number with increasing age, we report that the cINs are present through the entire animal lifespan. [ABSTRACT FROM AUTHOR]

During early development, brains undergo profound changes in structure at the molecular, synaptic, cellular and circuit level. At the same time, brains need to perform adaptive function. How do structurally immature brains process information? How do brains perform stable and reliable function despite massive changes in structure? The rodent olfactory system presents an ideal model for approaching these poorly understood questions. Rodents are born deaf and blind, and rely completely on their sense of smell to acquire resources essential for survival during the first 2 weeks of life, such as food and warmth. Here, we review decades of work mapping structural changes in olfactory circuits during early development, as well as more recent studies performing in vivo electrophysiological recordings to characterize functional activity patterns generated by these circuits. The findings demonstrate that neonatal olfactory processing relies on an interacting network of brain areas including the olfactory bulb and piriform cortex. Circuits in these brain regions exhibit varying degrees of structural maturity in neonatal animals. However, despite substantial ongoing structural maturation of circuit elements, the neonatal olfactory system produces dynamic network-level activity patterns that are highly stable over protracted periods during development. We discuss how these findings inform future work aimed at elucidating the circuit-level mechanisms underlying information processing in the neonatal olfactory system, how they support unique neonatal behaviors, and how they transition between developmental stages. [ABSTRACT FROM AUTHOR]

Objective: The current study aims to establish and evaluatee the kindling model of epilepsy induced by kainic acid (KA) microinjection into piriform cortex. Methods: Using c⁃fos immunofluorescence staining and TdT⁃mediated dUTP nick⁃end labeling (TUNEL)staining techniques to find the piriform cortex associated with epilepsy in a acute epilepsy mouse model. Racine score and seizure latency were observed after injection of KA in piriform cortex. Behavioral experiments were performed including testing the learning and memory abilities of mice in a water maze and the exploration ability of mice in a new object. The results of seizures and behavioral experiments were compared with the epileptic model of stereotactic injection of KA into the hippocampus. The electrical activities of new model mouse neurons were measured by electrophysiological techniques. Results: The results of c ⁃ fos immunofluorescence and TUNEL staining showed that in addition to the hippocampus, neurons in the piriform cortex and hippocampus were also significantly activated, and apoptosis occurred in the acute epilepsy mouse model. After injecting KA into the piriform cortex, the epilepsy was successfully ignited. Compared with the epilepsy model injected KA into the hippocampus, there was no significant difference in the epileptic seizure score and the seizurelatency was shorter. The behavioral results showed that the epileptic model mice induced by KA injection into the piriform cortex had a reduced spatial memory ability and a reduced ability to explore new objects. These results showed no significant difference compared to the epileptic model induced by KA injection into the hippocampus. The patch clamp recording test showed an increase in firing frequency and the resting membrane potential, and a decrease in amplitude of neuronal discharge. Conclusion: The microinjection of KA into the piriform cortex has successfully induced epilepsy, which may provide a new animal model for studying the pathogenesis of epilepsy. [ABSTRACT FROM AUTHOR]

Stress in the early period of life is an important factor predisposing to the development of pathology of the nervous system in animals and human beings in the late period of ontogenesis. We modeled early-life stress to assess the activation of the piriform cortex upon presentation of olfactory stimuli to experimental animals (CD1 mice of an age of 60 days and 10 months of postnatal development) and to evaluate marker expression of neurons with prolonged immaturity involved in plasticity processes of the adult brain and its recovery after injury. It has been established that early life stress reduces the number of immature neurons with DCX+PSA-NCAM+ phenotype in the piriform cortex and the response to olfactory-memory induction in the late period after stress. At the age of 60 days (P60), olfactory stimulation reduced sensitivity to unpleasant stimuli and stimulated the processes of short-term memory, while this effect is less pronounced at the age of 10 months. The results obtained indicate a possible contribution of immature neurons of the piriform cortex to the mechanisms of aberrant neuroplasticity in the late period of ontogenesis after early life stress. [ABSTRACT FROM AUTHOR]

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The olfactory tubercle (OT), which is a component of the olfactory cortex and ventral striatum, has functional domains that play a role in odor-guided motivated behaviors. Learning odor-guided attractive and aversive behavior activates the anteromedial (am) and lateral (l) domains of the OT, respectively. However, the mechanism driving learning-dependent activation of specific OT domains remains unknown. We hypothesized that the neuronal connectivity of OT domains is plastically altered through olfactory experience. To examine the plastic potential of synaptic connections to OT domains, we optogenetically stimulated intracortical inputs from the piriform cortex or sensory inputs from the olfactory bulb to the OT in mice in association with a food reward for attractive learning and electrical foot shock for aversive learning. For both intracortical and sensory connections, axon boutons that terminated in the OT domains were larger in the amOT than in the lOT for mice exhibiting attractive learning and larger in the lOT than in the amOT for mice exhibiting aversive learning. These results indicate that both intracortical and sensory connections to the OT domains have learning-dependent plastic potential, suggesting that this plasticity underlies learning-dependent activation of specific OT domains and the acquisition of appropriate motivated behaviors.

The recent identification of a population of non-newly born, prenatally generated “immature” neurons in the layer II of the piriform cortex (cortical immature neurons, cINs), raises questions concerning their maintenance or depletion through the lifespan. Most forms of brain structural plasticity progressively decline with age, a feature that is particularly prominent in adult neurogenesis, due to stem cell depletion. By contrast, the entire population of the cINs is produced during embryogenesis. Then these cells simply retain immaturity in postnatal and adult stages, until they “awake” to complete their maturation and ultimately integrate into neural circuits. Hence, the question remains open whether the cINs, which are not dependent on stem cell division, might follow a similar pattern of age-related reduction, or in alternative, might leave a reservoir of young, undifferentiated cells in the adult and aging brain. Here, the number and features of cINs were analyzed in the mouse piriform cortex from postnatal to advanced ages, by using immunocytochemistry for the cytoskeletal marker doublecortin. The abundance and stage of maturation of cINs, along with the expression of other markers of maturity/immaturity were investigated. Despite a marked decrease in this neuronal population during juvenile stages, reminiscent of that observed in hippocampal neurogenesis, a small amount of highly immature cINs persisted up to advanced ages. Overall, albeit reducing in number with increasing age, we report that the cINs are present through the entire animal lifespan.

During early development, brains undergo profound changes in structure at the molecular, synaptic, cellular and circuit level. At the same time, brains need to perform adaptive function. How do structurally immature brains process information? How do brains perform stable and reliable function despite massive changes in structure? The rodent olfactory system presents an ideal model for approaching these poorly understood questions. Rodents are born deaf and blind, and rely completely on their sense of smell to acquire resources essential for survival during the first 2 weeks of life, such as food and warmth. Here, we review decades of work mapping structural changes in olfactory circuits during early development, as well as more recent studies performing in vivo electrophysiological recordings to characterize functional activity patterns generated by these circuits. The findings demonstrate that neonatal olfactory processing relies on an interacting network of brain areas including the olfactory bulb and piriform cortex. Circuits in these brain regions exhibit varying degrees of structural maturity in neonatal animals. However, despite substantial ongoing structural maturation of circuit elements, the neonatal olfactory system produces dynamic network-level activity patterns that are highly stable over protracted periods during development. We discuss how these findings inform future work aimed at elucidating the circuit-level mechanisms underlying information processing in the neonatal olfactory system, how they support unique neonatal behaviors, and how they transition between developmental stages.

Epilepsies affecting the limbic regions are common and generate seizures often resistant to pharmacological treatment. Clinical evidence demonstrates that diverse regions of the mesial portion of the temporal lobe participate in limbic seizures; these include the hippocampus, the entorhinal, perirhinal and parahippocampal regions and the piriform cortex. The network mechanisms involved in the generation of olfactory-limbic epileptiform patterns will be here examined, with particular emphasis on acute interictal and ictal epileptiform discharges obtained by treatment with pro-convulsive drugs and by high-frequency stimulations on in vitro preparations, such as brain slices and the isolated guinea pig brain. The interactions within olfactory-limbic circuits can be summarized as follows: independent, region-specific seizure-like events (SLE) are generated in the olfactory and in the limbic cortex; SLEs generated in the hippocampal-parahippocampal regions tend to remain within these areas; the perirhinal region controls the neocortical propagation and the generalization of limbic seizures; interictal spiking in the olfactory regions prevents the invasion by SLEs generated in limbic regions.The potential relevance of these observations for human focal epilepsy is discussed.

Circuit operations of the olfactory bulb are modulated by higher order projections from multiple regions, many of which are themselves targets of bulbar output. Multiple glutamatergic regions project to the olfactory bulb, including the anterior olfactory nucleus (AON), prefrontal cortex (PFC), piriform cortex (PC), entorhinal cortex (EC), and tenia tecta (TT). In contrast, only one region provides GABAergic projections to the bulb. These GABA neurons are located in the horizontal limb of the diagonal band of Broca extending posteriorly through the magnocellular preoptic nucleus to the nucleus of the lateral olfactory bulb. However, it was unclear whether bulbar projecting GABAergic neurons collaterallize projecting to other brain regions. To address this, we mapped collateral projections from bulbar projecting GABAergic neurons using intersectional strategies of viral and traditional tract tracers. This approach revealed bulbar projecting GABAergic neurons show remarkable specificity targeting other primary olfactory cortical regions exhibiting abundant collateral projections into the accessory olfactory bulb, AON, PFC, PC, and TT. The only "nonolfactory" region receiving collateral projections was sparse connectivity to the medial prefrontal orbital cortex. This suggests that basal forebrain inhibitory feedback also modulates glutamatergic feedback areas that are themselves prominent bulbar projection regions. Thus, inhibitory feedback may be simultaneously modulating both synaptic processing of olfactory information in the bulb and associational processing of olfactory information from primary olfactory cortex. We hypothesize that these olfactory GABAergic feedback neurons are a regulator of the entire olfactory system. [ABSTRACT FROM AUTHOR]

Although olfactory deficits have been found in patients with early-stage Alzheimer's disease (AD), the underlying mechanisms remain unclear. Here we investigated whether and how human amyloid β (Aβ) oligomers affect neural activity in the piriform cortex (PC) slices of adult mice. We found that oligomeric Aβ1-42 decreased the excitability of pyramidal neurons in the anterior PC. The effect was not blocked by glutamate or GABA A receptor antagonists, suggesting that Aβ1-42-induced hypoactivity is independent of glutamatergic and GABAergic transmission. Interestingly, the hypoexcitability was occluded by serotonin (5-HT) and blocked by antagonists of 5-HT 2C receptors, phospholipase C (PLC), and calcium-activated potassium (BK) channels. Furthermore, Aβ1-42 oligomers failed to increase K+-channel currents in the presence of a BK channel blocker. Finally, 5-HT 2C receptor antagonist improved olfactory memory and odor discrimination in APP/PS1 mice. The above data indicate that Aβ disrupts olfactory information output from the PC via the 5-HT–5-HT 2C receptor–PLC–BK channel pathway. This study reveals that serotonergic modulation is a potential novel therapeutic target for olfactory damage in AD. [ABSTRACT FROM AUTHOR]

Abstract Background Low-density lipoprotein receptor-related protein 4 (LRP4) plays a critical role in the central nervous system (CNS), including hippocampal synaptic plasticity, maintenance of excitatory synaptic transmission, fear regulation, as well as long-term potentiation (LTP). Results In this study, we found that Lrp4 was highly expressed in layer II of the piriform cortex. Both body weight and brain weight decreased in Lrp4 ECD/ECD mice without TMD (Transmembrane domain) and ICD (intracellular domain) of LRP4. However, in the piriform cortical neurons of Lrp4 ECD/ECD mice, the spine density increased, and the frequency of both mEPSC (miniature excitatory postsynaptic current) and sEPSC (spontaneous excitatory postsynaptic current) was enhanced. Intriguingly, finding food in the buried food-seeking test was prolonged in both Lrp4 ECD/ECD mice and Lrp4 cKO (conditional knockout of Lrp4 in the piriform cortex) mice. Conclusions This study indicated that the full length of LRP4 in the piriform cortex was necessary for maintaining synaptic plasticity and the integrity of olfactory function.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development. • Brain-wide screen for prenatal neuronal activity highlights mouse piriform cortex • Embryonically active piriform neurons have hub-like connectivity ex vivo and in vivo • Neuropixels recordings show hub-like neurons lead population bursts in neonates • Altering neonatal hub-like neuronal activity modulates developing recurrent circuitry Using TRAP to perform a brain-wide screen for embryonically active neurons, Wang et al. identify and demonstrate the transient developmental role of activity in a hub-like neuronal population in promoting recurrent connectivity in the piriform cortex. These findings suggest a mechanism of activity-dependent maturation of intracortical circuits. [ABSTRACT FROM AUTHOR]

The potassium released in the extracellular space during neuronal activity is rapidly removed by glia and neurons to maintain tissue homeostasis. Oligodendrocyte-derived myelin axonal coating contributes to potassium buffering and is therefore crucial to control brain excitability. We studied activity-dependent extracellular potassium ([K+] o) changes in the piriform cortex (PC), a region that features highly segregated bundles of myelinated and unmyelinated fibers. Four-aminopyridine (4AP; 50 μM) treatment or patterned high-frequency stimulations (hfST) were utilized to generate [K+] o changes measured with potassium-sensitive electrodes in the myelinated lateral olfactory tract (LOT), in the unmyelinated PC layer I and in the myelinated deep PC layers in the ex vivo isolated guinea-pig brain. Seizure-like events induced by 4AP are initiated by the abrupt [K+] o rise in the layer I formed by unmyelinated fibers (Uva et al., 2017). Larger [K+] o shifts occurred in unmyelinated layers compared to the myelinated LOT. LOT hfST that mimicks pre-seizure discharges also generated higher [K+] o changes in unmyelinated PC layer I than in LOT and deep PC layers. The treatment with the Kir4.1 potassium channel blocker BaCl 2 (100 μM) enhanced the [K+] o changes generated by hfST in myelinated structures. Our data show that activity-dependent [K+] o changes are intrinsically different in myelinated vs unmyelinated cortical regions. The larger [K+] o shifts generated in unmyelinated structures may represent a vehicle for seizure generation. • [K+] o shifts were measured in myelinated and unmyelinated piriform cortex layers • Activity-dependent [K+] o changes are larger in unmyelinated structures • Blockade of Kir4.1 potassium channels enhanced [K+] o changes [ABSTRACT FROM AUTHOR]

Introduction. The control of the survival and differentiation of immature neurons in the piriform cortex of rodents, which can transform into GABAergic and/or glutamatergic neurons under the influence of olfactory stimuli, is an important factor for prevention of neurological dysfunction. The aim of the study was to assess the expression of GABAergic and glutamatergic neurons after olfactory stimulation (OS) in the mouse piriform cortex during postnatal development. Materials and methods. The study was carried out on CD1 male mice aged 2 (n = 20; group Р2), 21 (n = 20; group Р21) and 60 (n = 20; group Р60) days. The mice were presented with olfactory stimuli, and brain tissue was collected for immunohistochemical analysis 2 hours, 24 hours and 7 days later, to assess glutamic acid decarboxylase 67 (GAD67) and vesicular glutamate transporter 1 (VGlut1) expression. Results. OS in the group P2 animals increased VGlut1 expression in the first 2 hours after OS, followed by a return to baseline level by day 7, while GAD67 expression showed no significant changes. The animals in group P21 showed increased expression of VGlut1 and GAD67 two hours after OS, followed by a significant decrease. Expression of both molecules demonstrated a statistically significant increase in the group P60 animals 24 hours after OS, and remained at the same level on day 7 (GAD67) or returned to baseline levels (VGlut1). Conclusion. OS increases the number of GABAergic (GAD67+) и glutamatergic (VGlut1+) neurons in the piriform cortex (P60). The predominance of glutamatergic effects is a possible mechanism for associative memory cell recruitment.

Training rats in a particularly difficult olfactory discrimination task initiates a period of accelerated learning, manifested as a dramatic increase in the rats' capacity to discriminate between pairs of odors once they have learned the discrimination task, implying that rule learning has taken place. At the cellular biophysical level, rule learning is maintained by reduction in the conductance of the slow current (sIAHP) simultaneously in most piriform cortex layer II pyramidal neurons. Such sIAHP reduction is expressed in attenuation of the post-burst afterhyperpolarization (AHP) potential and thus in enhanced repetitive action potential firing. Previous studies have shown that a causal relationship exists between long-lasting post-burst AHP reduction and rule learning. A specific channel through which the sIAHP flows has not been identified. The sIAHP in pyramidal cells is critically dependent on membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)]. PtdIns(4,5)P(2) regulates the calcium sensitivity of the sIAHP by acting downstream from the rise in intracellular calcium. These findings led to the interesting hypothesis that PtdIns(4,5)P(2) activates a variety of potassium channels. Thus, the sIAHP would not represent a unitary ionic current but the embodiment of a generalized potassium channel gating mechanism. We thus hypothesized that the learning-induced increase in intrinsic excitability ismediated by reduced conductance of one ormore of the currents that contribute to the sIAHP. Here we first show, using current-clamp recordings, that the post-burst AHP in piriform cortex pyramidal neurons is also mediated by the Ih, and the contribution of this current to the post- burst AHP is also affected by learning. We also show, using whole-cell patch- clamp recordings, that the sIAHP in neurons from trained rats is not sensitive to blockingmembrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)], and to the blocking of the current mediated by the cholinergic muscarinic acetylcholine receptor (M-current). Further current-clamp recordings also show that blocking PtdIns(4,5)P(2) synthesis and application of a specific IKCa blocker have no effect on the post-burst AHP in neurons from trained as well as control rats. Taken together with results from our previous studies, these data suggest that rule learning-induced long-lasting enhancement in intrinsic neuronal excitability results from reduced conductance of the M-current and thus the slow potassium currents, which control repetitive spike firing. [ABSTRACT FROM AUTHOR]

Introduction: Resveratrol and related polyphenols have therapeutic effects ranging from treatment of depression, Alzheimer's and Parkinson's disease, obesity, diabetes, neurodegeneration and ageing. TRH and TRH‐like peptides, with the structure pGlu‐X‐Pro‐NH2, where 'X can be any amino acid reside, have reproductive, caloric‐restriction‐like, anti‐ageing, pancreatic‐β cell‐enhancing, cardiovascular and neuroprotective effects. We hypothesize that TRH and TRH‐like peptides are mediators of the therapeutic actions of the resveratrol derivative pterostilbene (PT). Methods: Sixteen young adult male Sprague–Dawley rats were divided into four groups. Control group remained on ad libitum chow and water for 10 days. Acute group received ad libitum chow and water for 9 days and then 0.9 g PT/250 g rat chow for 24 h. Chronic animals received PT in chow for 10 days. Withdrawal rats received PT chow for 8 days and then normal chow for 2 days. TRH and TRH‐like peptide levels were measured in medulla oblongata (MED), frontal cortex (FCX), hypothalamus (HY), amygdala (AY), hippocampus (HC), piriform cortex (PIR), nucleus accumbens (NA), entorhinal cortex (ENT), striatum (STR), cerebellum (CBL), anterior cingulate (ACNG), posterior cingulate (PCNG), prostate (PR), liver (L), testis (T), heart (H), pancreas (PAN), adrenals (AD) and epididymis (EP). Results: Significant changes in the levels of TRH and TRH‐like peptides occurred throughout the brain and peripheral tissues in response to PT treatment. Conclusion: The high responsiveness of PIR, CBL, HY, STR, PCNG, MED, FCX, NA, ACNG and AY in brain and EP and PR is consistent with TRH and TRH‐like peptides participating in the therapeutic effects of PT. [ABSTRACT FROM AUTHOR]

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory-olfactory integration using anatomical, electrophysiological, and optogenetic approaches, focusing on the auditory cortex as a key locus for cross-modal integration. First, retrograde and anterograde viral tracing strategies revealed a direct projection from the piriform cortex to the auditory cortex. Next, using in vivo electrophysiological recordings of neuronal activity in the auditory cortex of awake male or female mice, we found that odors modulate auditory cortical responses to sound. Finally, we used in vivo optogenetic manipulations during electrophysiology to demonstrate that olfactory modulation in auditory cortex, specifically, odor-driven enhancement of sound responses, depends on direct input from the piriform cortex. Together, our results identify a novel role of piriform-to-auditory cortical circuitry in shaping olfactory modulation in the auditory cortex, shedding new light on the neuronal mechanisms underlying auditory-olfactory integration., Competing Interests: Conflict of Interest: The authors declare no competing financial interests.

Odorous sensations are based on trigeminal and olfactory perceptions. Both trigeminal and olfactory stimuli generate overlapping as well as distinctive activations in the olfactory cortex including the piriform cortex. Orbitofrontal cortex (OFC), an integrative center for all senses, is directly activated in the presence of olfactory stimulations. In contrast, the thalamus, a very important midbrain structure, is not directly activated in the presence of odors, but rather acts as a relay for portions of olfactory information between primary olfactory cortex and higher-order processing centers. The aims of the study were (1) to examine the number of streamlines between the piriform cortex and the OFC and also between the piriform cortex and the thalamus and (2) to explore potential correlations between these streamlines and trigeminal and olfactory chemosensory perceptions. Thirty-eight healthy subjects were recruited for the study and underwent diffusion MRI using a 3T MRI scanner with 67 diffusion directions. ROIs were adapted from two studies looking into olfaction in terms of functional and structural properties of the olfactory system. The “waytotal number” was used which corresponds to number of streamlines between two regions of interests. We found the number of streamlines between the piriform cortex and the thalamus to be higher in the left hemisphere, whereas the number of streamlines between the piriform cortex and the OFC were higher in the right hemisphere. We also found streamlines between the piriform cortex and the thalamus to be positively correlated with the intensity of irritating (trigeminal) odors. On the other hand, streamlines between the piriform cortex and the OFC were correlated with the threshold scores for these trigeminal odors. This is the first studying the correlations between streamlines and olfactory scores using tractography. Results suggest that different chemosensory stimuli are processed through different networks in the chemosensory system involving the thalamus.

Training rats in a particularly difficult olfactory discrimination task initiates a period of accelerated learning, manifested as a dramatic increase in the rats' capacity to discriminate between pairs of odors once they have learned the discrimination task, implying that rule learning has taken place. At the cellular biophysical level, rule learning is maintained by reduction in the conductance of the slow current (sIAHP) simultaneously in most piriform cortex layer II pyramidal neurons. Such sIAHP reduction is expressed in attenuation of the post-burst afterhyperpolarization (AHP) potential and thus in enhanced repetitive action potential firing. Previous studies have shown that a causal relationship exists between long-lasting post-burst AHP reduction and rule learning. A specific channel through which the sIAHP flows has not been identified. The sIAHP in pyramidal cells is critically dependent on membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)]. PtdIns(4,5)P(2) regulates the calcium sensitivity of the sIAHP by acting downstream from the rise in intracellular calcium. These findings led to the interesting hypothesis that PtdIns(4,5)P(2) activates a variety of potassium channels. Thus, the sIAHP would not represent a unitary ionic current but the embodiment of a generalized potassium channel gating mechanism. We thus hypothesized that the learning-induced increase in intrinsic excitability is mediated by reduced conductance of one or more of the currents that contribute to the sIAHP. Here we first show, using current-clamp recordings, that the post-burst AHP in piriform cortex pyramidal neurons is also mediated by the Ih, and the contribution of this current to the post-burst AHP is also affected by learning. We also show, using whole-cell patch-clamp recordings, that the sIAHP in neurons from trained rats is not sensitive to blocking membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)], and to the blocking of the current mediated by the cholinergic muscarinic acetylcholine receptor (M-current). Further current-clamp recordings also show that blocking PtdIns(4,5)P(2) synthesis and application of a specific IKCa blocker have no effect on the post-burst AHP in neurons from trained as well as control rats. Taken together with results from our previous studies, these data suggest that rule learning-induced long-lasting enhancement in intrinsic neuronal excitability results from reduced conductance of the M-current and thus the slow potassium currents, which control repetitive spike firing.

Abstract Introduction Resveratrol and related polyphenols have therapeutic effects ranging from treatment of depression, Alzheimer's and Parkinson's disease, obesity, diabetes, neurodegeneration and ageing. TRH and TRH‐like peptides, with the structure pGlu‐X‐Pro‐NH2, where ‘X can be any amino acid reside, have reproductive, caloric‐restriction‐like, anti‐ageing, pancreatic‐β cell‐enhancing, cardiovascular and neuroprotective effects. We hypothesize that TRH and TRH‐like peptides are mediators of the therapeutic actions of the resveratrol derivative pterostilbene (PT). Methods Sixteen young adult male Sprague–Dawley rats were divided into four groups. Control group remained on ad libitum chow and water for 10 days. Acute group received ad libitum chow and water for 9 days and then 0.9 g PT/250 g rat chow for 24 h. Chronic animals received PT in chow for 10 days. Withdrawal rats received PT chow for 8 days and then normal chow for 2 days. TRH and TRH‐like peptide levels were measured in medulla oblongata (MED), frontal cortex (FCX), hypothalamus (HY), amygdala (AY), hippocampus (HC), piriform cortex (PIR), nucleus accumbens (NA), entorhinal cortex (ENT), striatum (STR), cerebellum (CBL), anterior cingulate (ACNG), posterior cingulate (PCNG), prostate (PR), liver (L), testis (T), heart (H), pancreas (PAN), adrenals (AD) and epididymis (EP). Results Significant changes in the levels of TRH and TRH‐like peptides occurred throughout the brain and peripheral tissues in response to PT treatment. Conclusion The high responsiveness of PIR, CBL, HY, STR, PCNG, MED, FCX, NA, ACNG and AY in brain and EP and PR is consistent with TRH and TRH‐like peptides participating in the therapeutic effects of PT.