Shank3 Deficiency Results in a Reduction in GABAergic Postsynaptic Puncta in the Olfactory Brain Areas.

Dysfunctional sensory systems, including altered olfactory function, have recently been reported in patients with autism spectrum disorder (ASD). Disturbances in olfactory processing can potentially result from gamma-aminobutyric acid (GABA)ergic synaptic abnormalities. The specific molecular mechanism by which GABAergic transmission affects the olfactory system in ASD remains unclear. Therefore, the present study aimed to evaluate selected components of the GABAergic system in olfactory brain regions and primary olfactory neurons isolated from Shank3-deficient (-/-) mice, which are known for their autism-like behavioral phenotype. Shank3 deficiency led to a significant reduction in GEPHYRIN/GABAAR colocalization in the piriform cortex and in primary neurons isolated from the olfactory bulb, while no change of cell morphology was observed. Gene expression analysis revealed a significant reduction in the mRNA levels of GABA transporter 1 in the olfactory bulb and Collybistin in the frontal cortex of the Shank3-/- mice compared to WT mice. A similar trend of reduction was observed in the expression of Somatostatin in the frontal cortex of Shank3-/- mice. The analysis of the expression of other GABAergic neurotransmission markers did not yield statistically significant results. Overall, it appears that Shank3 deficiency leads to changes in GABAergic synapses in the brain regions that are important for olfactory information processing, which may represent basis for understanding functional impairments in autism.

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity.

The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRABACh (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.

Neuron-Specific FMRP Roles in Experience-Dependent Remodeling of Olfactory Brain Innervation during an Early-Life Critical Period.

Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABAA signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder (ASD), manifests severe neurodevelopmental delays. Likewise, FXS disease models display disrupted neurodevelopmental critical periods. In the well-mapped Drosophila olfactory circuit model, perturbing the causative fragile X mental retardation protein (FMRP) within a single olfactory sensory neuron (OSN) class impairs odorant-dependent remodeling during an early-life critical period. Importantly, this impairment requires activation of other OSNs, and the olfactory circuit can compensate when FMRP is removed from all OSNs. Understanding the neuron-specific FMRP requirements within a developing neural circuit, as well as the FMRP loss compensation mechanisms, should help us engineer FXS treatments. This work suggests FXS treatments could use homeostatic mechanisms to alleviate circuit-level deficits.

Coordinated electrical activity in the olfactory bulb gates the oscillatory entrainment of entorhinal networks in neonatal mice.

Although the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system is functional at birth, controlling mother-offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC)-the gatekeeper of limbic circuitry-during neonatal development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell-dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC of anesthetized mice via axonal projections confined to upper cortical layers. Acute pharmacological silencing of OB activity diminishes entorhinal oscillations, whereas odor exposure boosts OB-entorhinal coupling at fast frequencies. Chronic impairment of olfactory sensory neurons disrupts OB-entorhinal activity. Thus, OB activity shapes the maturation of entorhinal circuits.

Pyramidal Cells in Olfactory Cortex.

The neocortex and olfactory cortices share many features including their laminar organization, developmental sequences, and cell types. Previous work indicates that neocortical pyramidal cells exhibit a gradient of dendritic size: cells involved in the initial processing of information are less complex than those in subsequent, higher processing areas. Results presented here confirm that the same is true for the olfactory cortex: pyramidal cells in the region closest to the olfactory bulb, the anterior olfactory nucleus, have smaller total dendritic length and occupy less neural space than those in the posterior piriform cortex. These findings add to the evidence for general rules of development, organization, and function across forebrain cortices.

Functional morphology of the primary olfactory centers in the brain of the hermit crab Coenobita clypeatus (Anomala, Coenobitidae).

Terrestrial hermit crabs of the genus Coenobita display strong behavioral responses to volatile odors and are attracted by chemical cues of various potential food sources. Several aspects of their sense of aerial olfaction have been explored in recent years including behavioral aspects and structure of their peripheral and central olfactory pathway. Here, we use classical histological methods and immunohistochemistry against the neuropeptides orcokinin and allatostatin as well as synaptic proteins and serotonin to provide insights into the functional organization of their primary olfactory centers in the brain, the paired olfactory lobes. Our results show that orcokinin is present in the axons of olfactory sensory neurons, which target the olfactory lobe. Orcokinin is also present in a population of local olfactory interneurons, which may relay lateral inhibition across the array of olfactory glomeruli within the lobes. Extensive lateral connections of the glomeruli were also visualized using the histological silver impregnation method according to Holmes-Blest. This technique also revealed the structural organization of the output pathway of the olfactory system, the olfactory projection neurons, the axons of which target the lateral protocerebrum. Within the lobes, the course of their axons seems to be reorganized in an axon-sorting zone before they exit the system. Together with previous results, we combine our findings into a model on the functional organization of the olfactory system in these animals.

The Fate of Transplanted Olfactory Progenitors Is Conditioned by the Cell Phenotypes of the Receiver Brain Tissue in Cocultures.

Among the numerous candidates for cell therapy of the central nervous system (CNS), olfactory progenitors (OPs) represent an interesting alternative because they are free of ethical concerns, are easy to collect, and allow autologous transplantation. In the present study, we focused on the optimization of neuron production and maturation. It is known that plated OPs respond to various trophic factors, and we also showed that the use of Nerve Growth Factor (NGF) allowed switching from a 60/40 neuron/glia ratio to an 80/20 one. Nevertheless, in order to focus on the integration of OPs in mature neural circuits, we cocultured OPs in primary cultures obtained from the cortex and hippocampus of newborn mice. When dissociated OPs were plated, they differentiated into both glial and neuronal phenotypes, but we obtained a 1.5-fold higher viability in cortex/OP cocultures than in hippocampus/OP ones. The fate of OPs in cocultures was characterized with different markers such as BrdU, Map-2, and Synapsin, indicating a healthy integration. These results suggest that the integration of transplanted OPs might by affected by trophic factors and the environmental conditions/cell phenotypes of the host tissue. Thus, a model of coculture could provide useful information on key cell events for the use of progenitors in cell therapy.

Additive Expression of Consolidated Memory through Drosophila Mushroom Body Subsets.

Associative olfactory memory in Drosophila has two components called labile anesthesia-sensitive memory and consolidated anesthesia-resistant memory (ARM). Mushroom body (MB) is a brain region critical for the olfactory memory and comprised of 2000 neurons that can be classified into αß, α'ß', and γ neurons. Previously we demonstrated that two parallel pathways mediated ARM consolidation: the serotonergic dorsal paired medial (DPM)-αß neurons and the octopaminergic anterior paired lateral (APL)-α'ß' neurons. This finding prompted us to ask how this composite ARM is retrieved. Here, we showed that blocking the output of αß neurons and that of α'ß' neurons each impaired ARM retrieval, and blocking both simultaneously had an additive effect. Knockdown of radish and octß2R in αß and α'ß' neurons, respectively, impaired ARM. A combinatorial assay of radish mutant background rsh1 and neurotransmission blockade confirmed that ARM retrieved from α'ß' neuron output is independent of radish. We identified MBON-ß2ß'2a and MBON-ß'2mp as the MB output neurons downstream of αß and α'ß' neurons, respectively, whose glutamatergic transmissions also additively contribute to ARM retrieval. Finally, we showed that α'ß' neurons could be functionally subdivided into α'ß'm neurons required for ARM retrieval, and α'ß'ap neurons required for ARM consolidation. Our work demonstrated that two parallel neural pathways mediating ARM consolidation in Drosophila MB additively contribute to ARM expression during retrieval.

Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain.

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain.

Analysis of Fos expression in the rat olfactory neurogenic region following single exposure to maternal separation during different neonatal stages.

Accumulating evidence confirms that the exposure of neonatal rats to maternal separation can significantly alter individual processes of postnatal neurogenesis in the olfactory neurogenic region - the subventricular zone (SVZ) and the rostral migratory stream (RMS). To establish the stressful influence of MS on postnatal neurogenesis we have investigated whether altered olfactory environment caused by short-term MS induces expression of Fos protein in the SVZ/RMS and in the olfactory cortical area - anterior olfactory nucleus (AON) of neonatal rats. Pups were separated from mothers for 2 hours at the postnatal days 7, 14 and 21. Immunohistochemically labeled Fos protein was assessed. Our results revealed that single exposure to MS is a stressful event that selectively and in age-dependent manner stimulates cellular activity in the SVZ and AON. A few Fos+ cells were found in the SVZ of P21 control animals and MS significantly increased their number. This suggests that some SVZ cells are included in the circuitry, which is activated by MS and that these cells have complete equipment for the Fos signal transduction. MS significantly increased the number of Fos+ cells in the AON in all age stages examined suggesting that its effect is mediated by olfaction.

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus.

AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of ß-amyloid (Aß) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Aß plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.

Localization and expression of molt-inhibiting hormone and nitric oxide synthase in the central nervous system of the green shore crab, Carcinus maenas, and the blackback land crab, Gecarcinus lateralis.

In decapod crustaceans, molting is controlled by the pulsatile release of molt-inhibiting hormone (MIH) from neurosecretory cells in the X-organ/sinus gland (XO/SG) complex in the eyestalk ganglia (ESG). A drop in MIH release triggers molting by activating the molting gland or Y-organ (YO). Post-transcriptional mechanisms ultimately control MIH levels in the hemolymph. Neurotransmitter-mediated electrical activity controls Ca2+-dependent vesicular release of MIH from the SG axon terminals, which may be modulated by nitric oxide (NO). In green shore crab, Carcinus maenas, nitric oxide synthase (NOS) protein and NO are present in the SG. Moreover, C. maenas are refractory to eyestalk ablation (ESA), suggesting other regions of the nervous system secrete sufficient amounts of MIH to prevent molting. By contrast, ESA induces molting in the blackback land crab, Gecarcinus lateralis. Double-label immunofluorescence microscopy and quantitative polymerase chain reaction were used to localize and quantify MIH and NOS proteins and transcripts, respectively, in the ESG, brain, and thoracic ganglion (TG) of C. maenas and G. lateralis. In ESG, MIH- and NOS-immunopositive cells were closely associated in the SG of both species; confocal microscopy showed that NOS was localized in cells adjacent to MIH-positive axon terminals. In brain, MIH-positive cells were located in a small number of cells in the olfactory lobe; no NOS immunofluorescence was detected. In TG, MIH and NOS were localized in cell clusters between the segmental nerves. In G. lateralis, Gl-MIH and Gl-crustacean hyperglycemic hormone (CHH) mRNA levels were ~105-fold higher in ESG than in brain or TG of intermolt animals, indicating that the ESG is the primary source of these neuropeptides. Gl-NOS and Gl-elongation factor (EF2) mRNA levels were also higher in the ESG. Molt stage had little or no effect on CHH, NOS, NOS-interacting protein (NOS-IP), membrane Guanylyl Cyclase-II (GC-II), and NO-independent GC-III expression in the ESG of both species. By contrast, MIH and NO receptor GC-I beta subunit (GC-Iß) transcripts were increased during premolt and postmolt stages in G. lateralis, but not in C. maenas. MIH immunopositive cells in the brain and TG may be a secondary source of MIH; the release of MIH from these sources may contribute to the difference between the two species in response to ESA. The MIH-immunopositive cells in the TG may be the source of an MIH-like factor that mediates molt inhibition by limb bud autotomy. The association of MIH- and NOS-labeled cells in the ESG and TG suggests that NO may modulate MIH release. A model is proposed in which NO-dependent activation of GC-I inhibits Ca2+-dependent fusion of MIH vesicles with the nerve terminal membrane; the resulting decrease in MIH activates the YO and the animal enters premolt.

The Pig Olfactory Brain: A Primer.

Despite the fact that pigs are reputed to have excellent olfactory abilities, few studies have examined regions of the pig brain involved in the sense of smell. The present study provides an overview of the olfactory bulb, anterior olfactory nucleus, and piriform cortex of adult pigs using several approaches. Nissl, myelin, and Golgi stains were used to produce a general overview of the organization of the regions and confocal microscopy was employed to examine 1) projection neurons, 2) GABAergic local circuit neurons that express somatostatin, parvalbumin, vasoactive intestinal polypeptide, or calretinin, 3) neuromodulatory fibers (cholinergic and serotonergic), and 4) glia (astrocytes and microglia). The findings revealed that pig olfactory structures are quite large, highly organized and follow the general patterns observed in mammals.

Fez family transcription factors: controlling neurogenesis and cell fate in the developing mammalian nervous system.

Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types.

Activation of the central but not the medial and cortical amygdala during anticipation for daily nursing in the rabbit.

Rabbits have remarkable nursing behavior: after parturition, does visit daily their pups for nursing only once with circadian periodicity. Before the nursing events, they present increased activity and arousal, which shift according to the timing of scheduled nursing, either during the day or night. Brain areas related to maternal behavior and neuroendocrine cells for milk secretion are also entrained. The daily return of the doe for nursing at approximately the same hour suggests a motivational drive with circadian periodicity. Previously, we reported the activation of the mesolimbic system at the time of nursing, but not 12 h before that. Aiming at a better understanding of the mechanism of this anticipatory behavior, we explored the participation of the limbic regions of the amygdala and the bed nucleus of the stria terminalis, as well as the possible activation of the hypothalamic-pituitaryadrenal axis, specifically the corticotropin-releasing factor cells in the hypothalamic paraventricular nucleus of does at different times before and after nursing. The medial and cortical amygdala, the bed nucleus of the stria terminalis, and corticotropin cells showed activation only after nursing. However, the central amygdala was also activated before nursing. We conclude that the medial and the cortical amygdala form part of the afferent olfactory pathway for entrainment, and the central amygdala participates in the anticipatory motivational circuit of the control of periodic nursing. The lack of activation of corticotropin cells before nursing is consistent with the possible harmful effects of the doe's high glucocorticoid levels on the developing pups.

Adenosine A2A receptor neurons in the olfactory bulb mediate odor-guided behaviors in mice.

Depression, rapid eye movement (REM) sleep behavior disorder, and altered olfaction are often present in Parkinson's disease. Our previous studies demonstrated the role of the olfactory bulb (OB) in causing REM sleep disturbances in depression. Furthermore, adenosine A2A receptors (A2AR) which are richly expressed in the OB, play an important role in the regulation of REM sleep. Caffeine, an adenosine A1 receptors and A2AR antagonist, and other A2AR antagonists were reported to improve olfactory function and restore age-related olfactory deficits. Therefore, we hypothesized that the A2AR neurons in the OB may regulate olfaction or odor-guided behaviors in mice. In the present study, we employed chemogenetics to specifically activate or inhibit neuronal activity. Then, buried food test and olfactory habituation/dishabituation test were performed to measure the changes in the mice's olfactory ability. We demonstrated that activation of OB neurons or OB A2AR neurons shortened the latency of buried food test and enhanced olfactory habituation to the same odors and dishabituation to different odors; inhibition of these neurons showed the opposite effects. Photostimulation of ChR2-expressing OB A2AR neuron terminals evoked inward current in the olfactory tubercle (OT) and the piriform cortex (Pir), which was blocked by glutamate receptor antagonists 2-amino-5-phosphonopentanoic acid and 6-cyano-7nitroquinoxaline-2,3-dione. Collectively, these results suggest that the OB mediates olfaction via A2AR neurons in mice. Moreover, the excitatory glutamatergic release from OB neurons to the OT and the Pir were found responsible for the olfaction-mediated effects of OB A2AR neurons.

Histamine H1 receptors regulate anhedonic-like behavior in rats: Involvement of the anterior cingulate and lateral entorhinal cortices.

A decreased H1 receptor activity is observed in the anterior cingulate cortex (aCgCx) of depressed patients. The role of this abnormality in the development of depression-related processes is unstudied. We examined the influence of a decreased brain H1 receptor activity on rat behavior in the sucrose preference test. The H1 receptor deficit was simulated by injection of an H1 antagonist into the aCgCx; also, two aCgCx projection areas, lateral and medial entorhinal cortices were examined. A blockade of H1-receptors in the aCgCx and lateral entorhinal cortex (LEntCx) significantly reduced sucrose preference. These findings suggest the existence of H1 receptor-mediated aCgCx-LEntCx circuitry mechanism regulating anhedonic-like behavior in rats. The presented data suggest that H1 receptor-mediated processes might be a therapeutic target in depressive disorders.

Post-traumatic olfactory loss and brain response beyond olfactory cortex.

Olfactory impairment after a traumatic impact to the head is associated with changes in olfactory cortex, including decreased gray matter density and decreased BOLD response to odors. Much less is known about the role of other cortical areas in olfactory impairment. We used fMRI in a sample of 63 participants, consisting of 25 with post-traumatic functional anosmia, 16 with post-traumatic hyposmia, and 22 healthy controls with normosmia to investigate whole brain response to odors. Similar neural responses were observed across the groups to odor versus odorless stimuli in the primary olfactory areas in piriform cortex, whereas response in the frontal operculum and anterior insula (fO/aI) increased with olfactory function (normosmia > hyposmia > functional anosmia). Unexpectedly, a negative association was observed between response and olfactory perceptual function in the mediodorsal thalamus (mdT), ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (pCC). Finally, connectivity within a network consisting of vmPFC, fO, and pCC could be used to successfully classify participants as having functional anosmia or normosmia. We conclude that, at the neural level, olfactory impairment due to head trauma is best characterized by heightened responses and differential connectivity in higher-order areas beyond olfactory cortex.

α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the Parkinson's disease olfactory bulb.

Reduced olfactory function (hyposmia) is one of the most common non-motor symptoms experienced by those living with Parkinson's disease (PD), however, the underlying pathology of the dysfunction is unclear. Recent evidence indicates that α-synuclein (α-syn) pathology accumulates in the anterior olfactory nucleus of the olfactory bulb years before the motor symptoms are present. It is well established that neuronal cells in the olfactory bulb are affected by α-syn, but the involvement of other non-neuronal cell types is unknown. The occurrence of intracellular α-syn inclusions were quantified in four non-neuronal cell types - microglia, pericytes, astrocytes and oligodendrocytes as well as neurons in the anterior olfactory nucleus of post-mortem human PD olfactory bulbs (n = 11) and normal olfactory bulbs (n = 11). In the anterior olfactory nucleus, α-syn inclusions were confirmed to be intracellular in three of the four non-neuronal cell types, where 7.78% of microglia, 3.14% of pericytes and 1.97% of astrocytes were affected. Neurons containing α-syn inclusions comprised 8.60% of the total neuron population. Oligodendrocytes did not contain α-syn. The data provides evidence that non-neuronal cells in the PD olfactory bulb contain α-syn inclusions, suggesting that they may play an important role in the progression of PD.

Context-dependent odor learning requires the anterior olfactory nucleus.

Learning to associate the context in which a stimulus occurs is an important aspect of animal learning. We propose that the association of an olfactory stimulus with its multisensory context is mediated by projections from ventral hippocampus (vHC) networks to the anterior olfactory nucleus (AON). Using a contextually cued olfactory discrimination task, rats were trained to associate 2 olfactory stimuli with different responses depending on visuospatial context. Temporary lesions of the AON or vHC impaired performance on this task. In contrast, such lesions did not impair performance on a noncontextual olfactory discrimination task. Moreover, vHC lesions also impaired performance on an analogous contextually cued texture discrimination task, whereas AON lesions affected only olfactory contextual associations. We describe a distinct role for the AON in olfactory processing and conclude that early olfactory networks such as the olfactory bulb and AON function as multimodal integration networks rather than processing olfactory signals exclusively. (PsycInfo Database Record (c) 2020 APA, all rights reserved).