Piriform Cortex Research Articles

Scaling Principles of Distributed Circuits

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 (ormitral 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∼g3/2. 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 nichewithout designing developmental programs de novo. These principles might apply to other distributed circuits like the hippocampus.

CB1 Receptors in the Anterior Piriform Cortex Control Odor Preference Memory

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 endocannabinoidsignaling is selective for retrieval of appetitive memory. Anatomical investigations revealed thatCB1 receptors are highly expressed on aPC GABAergic interneurons, and exvivo 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.

A New Ensemble Learning Framework for 3D Biomedical Image Segmentation

3D image segmentation plays an important role in biomedical image analysis. Many 2D and 3D deep learning models have achieved state-of-the-art segmentation performance on 3D biomedical image datasets. Yet, 2D and 3D models have their own strengths and weaknesses, and by unifying them together, one may be able to achieve more accurate results. In this paper, we propose a new ensemble learning framework for 3D biomedical image segmentation that combines the merits of 2D and 3D models. First, we develop a fully convolutional network based meta-learner to learn how to improve the results from 2D and 3D models (base-learners). Then, to minimize over-fitting for our sophisticated meta-learner, we devise a new training method that uses the results of the baselearners as multiple versions of “ground truths”. Furthermore, since our new meta-learner training scheme does not depend on manual annotation, it can utilize abundant unlabeled 3D image data to further improve the model. Extensive experiments on two public datasets (the HVSMR 2016 Challenge dataset and the mouse piriform cortex dataset) show that our approach is effective under fully-supervised, semisupervised, and transductive settings, and attains superior performance over state-of-the-art image segmentation methods.

Coactivations of barrel and piriform cortices induce their mutual synapse innervations and recruit associative memory cells

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.

OLFACTORY DEFICITS AND FUNCTIONAL CONNECTIVITY DISRUPTIONS IN PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE (SCD)

Patients with subjective cognitive decline (SCD) are the high risk group for developing Alzheimer's disease (AD). Olfactory fMRI)was used to investigate olfactory activation and connectivity in SCD and cognitively normal (CN) adults, and to explore early functional markers for AD. Twenty SCD participants and 20 age-, education-level-matched CN elderly were recruited. Full set of neurocognitive tests, olfactory threshold and identification battery tests (Osmic Enterprise, LLC), and olfactory fMRI were administered to each participant. The differences in olfactory behavior scores, neuropsychological scales, and task-fMRI brain activation maps between the two groups were analyzed, and the correlation between brain activation and olfactory behavior scores was evaluated. Brain regions, which had significant different activations were used as seeds for resting-state functional connection analysis. There was no statistically significant difference in olfactory threshold between SCD and CN subjects, but SCD showed a significant decrease in olfactory identification ability (p < 0.05). There was also a significant decrease (p < 0.05) in the SCD self-rating scale, the immediate and delayed test of Philadelphia verbal learning, while the remaining neuropsychological scales were within normal range. In the olfactory fMRI, activation in bilateral primary olfactory cortex was significantly reduced in SCD patients, including bilateral entorhinal cortex, amygdala, piriform cortex, anterior olfactory nucleus, and head of the hippocampus (Fig. 1). The resting-state functional connectivity with the bilateral primary olfactory cortex (POC) showed that the functional connections between the POC and frontal cortex and the default mode network (DMN) were significantly weakened in the SCD patients (Fig. 2 and 3, AlphaSim correction with voxel level p<0.01 and cluster level p<0.05).

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

The ability to recognize and identify a smell is highly dependent on multisensory context and expectation, for example, hearing the name of the odor source. Here, we develop a novel auditory-odor association task in rats, wherein the animal learns that a specific auditory tone, when associated with a specific odor, predicts reward (Go signal), whereas the same tone associated with a different odor, or vice versa, is not (No-Go signal). The tone occurs prior to the onset of the odor, allowing physiological analyses of sensory-evoked local field potential (LFP) activity to each stimulus in primary auditory cortex and anterior piriform cortex (aPCX). In trained animals that have acquired the task, both auditory and subsequent olfactory cues activate 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.

Multiunit cluster firing patterns of piriform cortex and mediodorsal thalamus in absence epilepsy

ObjectiveThe objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. MethodsMultiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. ResultsThere were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking −0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. ConclusionsBoth the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity.

Genetic absence epilepsy: Effective connectivity from piriform cortex to mediodorsal thalamus

ObjectiveThe objective of the study was to quantify effective connectivity from the piriform cortex to mediodorsal thalamus, in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). MethodsLocal field potentials (LFPs) were recorded using microelectrode arrays implanted in the mediodorsal thalamus and piriform cortex, in three urethane anesthetized GAERS and three control rats. Screw electrodes were placed in the primary motor cortex to identify epileptiform discharges. We used transfer entropy to measure effective connectivity from piriform cortex to mediodorsal thalamus prior to and during generalized epileptiform discharges. ResultsWe observed increased theta band effective connectivity from piriform cortex to mediodorsal thalamus, prior to and during epileptiform discharges in GAERS compared with controls. Increased effective connectivity was also observed in beta and gamma bands from the piriform cortex to mediodorsal thalamus, but only during epileptiform discharges. ConclusionsThis preliminary study suggests that increased effective theta connectivity from the piriform cortex to the mediodorsal thalamus may be a feature of the ‘epileptic network’ associated with genetic absence epilepsy. Our findings indicate an underlying predisposition of this direct pathway to propagate epileptiform discharges in genetic absence epilepsy.

Active information maintenance in working memory by a sensory cortex.

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.

Olfactory function in focal epilepsies: Understanding mesial temporal lobe epilepsy beyond the hippocampus.

Several lines of research have linked olfactory regions with the pathophysiology of focal epilepsies. Among those regions, the piriform cortex represents the major part of the primary olfactory cortex. According to these data, we raised the hypothesis that in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that could be more significant compared to patients with extra‐hippocampal focal epilepsy and healthy controls. This could be the consequence of a dysfunctional epileptogenic network that extends beyond the hippocampus and affects other structures, including the piriform cortex. To test this hypothesis, we evaluated the olfactory function with the Sniffin' Sticks test in 32 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis, 30 patients with extra‐hippocampal focal epilepsy, and 22 healthy controls. Compared to the other study groups, patients with temporal lobe epilepsy due to hippocampal sclerosis showed a basal olfactory dysfunction characterized by an impairment in odor discrimination and odor identification. We also found that high seizure frequency had a strong correlation with the evaluated olfactory tasks. Our results are consistent with neuroimaging and neuropathological data that establish a link between olfactory regions and the pathophysiology of temporal lobe epilepsy.

This is safe, you can eat it

Neuroscience Social transmission of food preference is a model for studying nonspatial memory. In mice, a signal that food is safe to eat is transmitted by its smell along with molecules in the breath of a conspecific. How the odor itself is encoded and assigned valence is poorly understood. Loureiro et al. found a monosynaptic pathway between two brain areas, the piriform cortex and the medial prefrontal cortex, that plays a central role in this process. This connection strengthens during social interaction, thereby allowing a mouse to provide a food safety message to its companion. Science , this issue p. [991][1] [1]: /lookup/doi/10.1126/science.aaw5842

Social transmission of food safety depends on synaptic plasticity in the prefrontal cortex.

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.

Olfactory receptor neurons express olfactory marker protein but not calpain 5 from the same genomic locus

Gene expression is highly regulated to functionally diversify cells. Genes that cooperate in the same physiological processes occasionally reside within nearby regions in a chromosome. Olfactory marker protein (OMP) is highly expressed in mature olfactory receptor neurons (ORNs), but its physiological roles are not fully understood. According to the genomic map, the OMP gene is located within an intron of the calcium-dependent protease, calpain 5 (CAPN5); in other words, the OMP gene is a nested intronic gene. Thus, we attempted to investigate the gene expression and protein distribution of CAPN5 in the olfactory epithelium compared with that in the central nervous system (CNS). By performing reverse-transcriptase PCR and in situ hybridization, we confirmed that CAPN5 mRNA was expressed in the olfactory epithelium. We then performed immunohistological investigations using sliced preparations obtained from mice expressing GFP under OMP promoter activity. The detected GFP fluorescence was restricted to the knob, soma and axon bundles of the ORNs, while CAPN5 immunoreactivity (CAPN5-IR) was ubiquitously detected in the olfactory epithelial layer and lamina propria; signals were strongly detected in the supporting cells within the epithelium. In the CNS, CAPN5 signals were widely detected and were especially strong in the hippocampal formation and the piriform cortex as previously indicated. Therefore, these data indicate that ORNs express OMP but not CAPN5 from CAPN5 gene expression even though they are localized in the same genomic locus. The mechanisms by which the OMP promoter is regulated require detailed investigations.

1804-P: Characterizing Central Olfactory Circuits Modulating Energy Homeostasis

Olfactory inputs are important for hedonic evaluation of food, resulting in food choice and possible consumption. Olfactory acuity is determined by the feeding status, with hunger enhancing smell and food seeking behavior, whereas satiety suppresses olfaction and promotes energy expenditure. Efforts to understand the cellular basis of food intake and energy expenditure revealed the crucial role of the hypothalamus as a master regulator of whole-body energy homeostasis, integrating internal and external stimuli to modulate energy intake and expenditure accordingly. However, how the hypothalamus adjusts circuits regulating energy homeostasis depending on external stimuli, such as smell, remains an intriguing mystery. Our previous work revealed that ablation of olfactory sensory neurons (OSNs) stimulates hypothalamic-driven autonomic tone and promotes catabolic pathways, enhancing thermogenesis in adipose tissue. These findings unravel a new function for the olfactory system in controlling energy homeostasis in response to sensory signals. Here, we analyzed neural circuits connecting olfaction and hypothalamus and determined the role of olfactory inputs on energy homeostasis. To identify neural circuits linking olfactory and hypothalamic neurons, we conducted anterograde viral tracing from mitral cell layer in the main olfactory bulb (MOB) in Tbx21-Cre mice and retrograde viral tracing from pro-opiomelanoctin (POMC)- and agouti-related protein (AgRP)-expressing hypothalamic neurons in POMC-Cre and AgRP-IRES-Cre mice using Cre-dependent helper virus and modified rabies virus. Additionally, we used chemical ablation of mature OSNs and chemogenetic silencing of mitral cell layer neurons to determine the effect of olfaction on energy homeostasis. Our data suggest that piriform cortex (PC)-amygdala (Amy)-arcuate nucleus of hypothalamus (ARC) is one of the plausible circuits responsible for transferring signals from MOB to the hypothalamus. Disclosure C. Riera: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-12)

Distribution of GABAergic Neurons and VGluT1 and VGAT Immunoreactive Boutons in the Ferret (Mustela putorius) Piriform Cortex and Endopiriform Nucleus. Comparison With Visual Areas 17, 18 and 19.

We studied the cellular organization of the piriform network [comprising the piriform cortex (PC) and endopiriform nucleus (EP)] of the ferret (Mustela putorius)—a highly excitable region prone to seizures—and, more specifically, the distribution and morphology of different types of gamma-aminobutyric acid (GABA)ergic neurons, and the distribution and ratio of glutamatergic and GABAergic boutons, and we compared our findings to those in primary visual area 17, and secondary areas 18 and 19. We accomplished this by using cytochrome oxidase and immunohistochemistry for mature neuronal nuclei (NeuN), GABAergic neurons [glutamic acid decarboxylase-67 (GAD67), calretinin (CR) and parvalbumin (PV)], and for excitatory (vesicular glutamate transporter 1; VGluT1) and inhibitory (vesicular GABA transporter; VGAT) boutons. In the ferret, the cellular organization of the piriform network is similar to that described in other species such as cats, rats and opossums although some differences also exist. GABAergic immunolabeling showed similarities between cortical layers I–III of the PC and visual areas, such as the relative distribution of GABAergic neurons and the density and area of VGluT1- and VGAT-immunoreactive boutons. However, multiple differences between the piriform network and visual areas (layers I–VI) were found, such as the percentage of GABAergic neurons with respect to the total number of neurons and the ratio of VGluT1- and VGAT-immunoreactive boutons. These findings are relevant to better understand the high excitability of the piriform network.

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus.

Status epilepticus (SE, a prolonged seizure activity) impairs brain-blood barrier (BBB) integrity, which results in secondary complications following SE. The non-integrin 67-kDa laminin receptor (67-kDa LR) plays a role in cell adherence to laminin (a major glycoprotein component in basement membrane), and participates laminin-mediated signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK). Thus, we investigated the role of 67-kDa LR in SE-induced vasogenic edema formation in the rat piriform cortex (PC). SE diminished 67-kDa LR expression, but increased laminin expression, in endothelial cells accompanied by the reduced SMI-71 (a rat BBB barrier marker) expression. Astroglial 67-kDa LR expression was also reduced in the PC due to massive astroglial loss. 67-kDa LR neutralization led to serum extravasation in the PC concomitant with the reduced SMI-71 expression. 67-kDa LR neutralization also decreased expressions of dystrophin and aquaporin-4 (AQP4). In addition, it increased p38 MAPK phosphorylation and expressions of vascular endothelial growth factor (VEGF), laminin and endothelial nitric oxide synthase (eNOS), which were abrogated by SB202190, a p38 MAPK inhibitor. Therefore, our findings indicate that 67-kDa LR dysfunction may disrupt dystrophin-AQP4 complex, which would evoke vasogenic edema formation and subsequent laminin over-expression via activating p38 MAPK/VEGF axis.

Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain

Although deep brain stimulation of the entorhinal cortex has recently shown promise in the treatment of early forms of cognitive decline, the underlying neurophysiological processes remain elusive. Therefore, the lateral entorhinal cortex (LEC) was stimulated with trains of continuous 5 Hz and 20 Hz pulses or with bursts of 100 Hz pulses to visualize activated neuronal networks, i.e., neuronal responses in the dentate gyrus and BOLD responses in the entire brain were simultaneously recorded. Electrical stimulation of the LEC caused a wide spread pattern of BOLD responses. Dependent on the stimulation frequency, BOLD responses were only triggered in the amygdala, infralimbic, prelimbic, and dorsal peduncular cortex (5 Hz), or in the nucleus accumbens, piriform cortex, dorsal medial prefrontal cortex, hippocampus (20 Hz), and contralateral entorhinal cortex (100 Hz). In general, LEC stimulation caused stronger BOLD responses in frontal cortex regions than in the hippocampus. Identical stimulation of the perforant pathway, a fiber bundle projecting from the entorhinal cortex to the dentate gyrus, hippocampus proper, and subiculum, mainly elicited significant BOLD responses in the hippocampus but rarely in frontal cortex regions. Consequently, BOLD responses in frontal cortex regions are mediated by direct projections from the LEC rather than via signal propagation through the hippocampus. Thus, the beneficial effects of deep brain stimulation of the entorhinal cortex on cognitive skills might depend more on an altered prefrontal cortex than hippocampal function.

Epigenetic and autophagic changes after nerve agent exposure in the rat piriform cortex and hippocampus

The detrimental effects of organophosphate (OP) nerve agents have been reported but the mechanisms mediating these multiple effects are not well understood. Recent use of nerve agents in Syria and the UK illustrate their continuous threat to the modern world. Epigenetic and autophagy studies are useful to address the issues related to regulation of gene and protein expression by which nerve agents could impact on human health. These studies help to understand molecular mechanisms underlying the multiple neurotoxic effects of nerve agents. In the present study, changes in epigenetic (global DNA methylation and histone acetylation) and autophagic marker proteins were studied in the nerve agent sensitive rat brain areas (piriform cortex and hippocampus) after soman (1xLD50) exposure. Global DNA methylation analysis revealed that nerve agent induced hypomethylation in the brain regions at 1 and 7 days post exposure. In contrast, DNA hypermethylation was observed at 30 days post soman exposure, demonstrating a possible compensatory mechanism. Western blot analysis showed significant increase in the histone acetylation levels after soman exposure in the piriform cortex and hippocampus. The present study observed the changes in autophagic proteins of nerve agent poisoning for the first time to the best of our knowledge. Immunoreactivity levels of autophagic proteins (LC3-II, ATG-5 and p62) were transiently increased in the rat piriform cortex and hippocampus after soman exposure. In conclusion, this study provides insight into the epigenetic and autophagic changes in the brain following soman exposure and their possible role in the neuronal damage and development of multiple neurological effects.

Cortical Organization of Centrifugal Afferents to the Olfactory Bulb: Mono- and Trans-synaptic Tracing with Recombinant Neurotropic Viral Tracers.

Sensory processing is strongly modulated by different brain and behavioral states, and this is based on the top-down modulation. In the olfactory system, local neural circuits in the olfactory bulb (OB) are innervated by centrifugal afferents in order to regulate the processing of olfactory information in the OB under different behavioral states. The purpose of the present study was to explore the organization of neural networks in olfactory-related cortices and modulatory nuclei that give rise to direct and indirect innervations to the glomerular layer (GL) of the OB at the whole-brain scale. Injection of different recombinant attenuated neurotropic viruses into the GL showed that it received direct inputs from each layer in the OB, centrifugal inputs from the ipsilateralanterior olfactory nucleus (AON), anterior piriform cortex (Pir), and horizontal limb of diagonal band of Broca (HDB), and various indirect inputs from bilateral cortical neurons in the AON, Pir, amygdala, entorhinal cortex, hippocampus, HDB, dorsal raphe, median raphe and locuscoeruleus. These results provide a circuitry basis that will help further understand the mechanism by which olfactory information-processing in the OB is regulated.

Olanzapine exposure diminishes perfusion and decreases volume of sensorimotor cortex in rats.

Olanzapine is a frequently used atypical antipsychotic drug known to exert structural brain alterations in animals. This study investigated whether chronic olanzapine exposure alters regional blood brain perfusion assessed by Arterial Spin Labelling (ASL) magnetic resonance imaging (MRI) in a validated model of olanzapine-induced metabolic disturbances. An effect of acute olanzapine exposure on brain perfusion was also assessed for comparison. Adult Sprague-Dawley female rats were treated by intramuscular depot olanzapine injections (100 mg/kg every 14 days) or vehicle for 8 weeks. ASL scanning was performed on a 9.4 T Bruker BioSpec 94/30USR scanner under isoflurane anesthesia. Serum samples were used to assay leptin and TNF-α level while brains were sliced for histology. Another group received only one non-depot intraperitoneal dose of olanzapine (7 mg/kg) during MRI scanning, thus exposing its acute effect on brain perfusion. Both acute and chronic dosing of olanzapine resulted in decreased perfusion in the sensorimotor cortex, while no effect was observed in the piriform cortex or hippocampus. Furthermore, in the chronically treated group decreased cortex volume was observed. Chronic olanzapine dosing led to increased body weight, adipose tissue mass and leptin level, confirming its expected metabolic effects. This study demonstrates region-specific decreases in blood perfusion associated with olanzapine exposure present already after the first dose. These findings extend our understanding of olanzapine-induced functional and structural brain changes.