APOE \u03b54 Carriage is Associated with Hippocampus-Olfactory Tract Functional Connectivity

Assessment of direct knowledge of the human olfactory system

We examined brain-derived neurotrophic factor (BDNF) mRNA expression across the olfactory system following fear conditioning. Mice received 10 pairings of odor with footshock or equivalent unpaired odors and shocks. We found increased BDNF mRNA in animals receiving paired footshocks in the multiple regions examined including the posterior piriform cortex (PPC) and basolateral amygdala (BLA). This was in contrast to the unpaired and odor-alone treatments, where BDNF mRNA was increased in the olfactory bulb (OB) and anterior piriform cortex (APC) only, but not the higher olfactory areas. We propose that odor exposure increases expression of BDNF in the OB and APC while the PPC and BLA increase BDNF mRNA only when associative learning occurs.

The orbitofrontal cortex (OFC) has been characterized as a higher-order, multimodal sensory cortex. Evidence from electrophysiological and behavioral studies in the rat has suggested that OFC plays a role in modulating olfactory guided behavior, and a significant projection to OFC arises from piriform cortex, the traditional primary olfactory cortex. To discern how OFC interacts with primary olfactory structures, the anterograde tracer Phaseolus vulgaris leucoagglutinin was injected into orbitofrontal cortical areas in adult male rats. Labeled fibers were found in the piriform cortex and olfactory bulb on the side ipsilateral to the injection. Notably, the projection to piriform cortex was predominantly from ventrolateral orbital cortex, and was not uniform; rostrally, the projection to the ventral portion of the anterior piriform cortex (APC) was substantial, while the dorsal APC was virtually free of labeled fibers. Labeled fibers were found in both the dorsal and ventral portions in more caudal regions of APC. Most labeled fibers were found in layer III, although a substantial number of fibers were observed in layers Ib and II. Labeled fibers in posterior piriform cortex also were seen after injection into orbitofrontal areas. Taken together with previous reports, these findings suggest that piriform cortex includes multiple subdivisions, which may perform separate, parallel functions in olfactory information processing. Further, these results suggest that the OFC, in addition to its putative role in encoding information about the significance of olfactory stimuli, may play a role in modulating odor response properties of neurons in piriform cortex.

BackgroundAllergic rhinitis (AR) has been identified as a cause of olfactory dysfunction. Beyond the classic symptoms, AR has been associated with altered sleep patterns, a decline in cognitive performance and higher likelihood of depression and anxiety. The olfactory pathway has been postulated to be a possible link between nasal inflammation and central nervous system (CNS) modifications. Thus, we aimed to investigate the structural, functional and behavioral changes in the olfactory pathway and related areas in an animal model of AR. MethodsAR was induced in adult Wistar rats by ovalbumin sensitization and challenge. Following olfactory and behavioral tests we investigated the synaptic structure of the olfactory bulb (OB), anterior olfactory nuclei (AON), piriform cortex and prefrontal cortex (PFC), by immunofluorescence detection of synaptophysin (Syn) and glutamatergic, GABAergic and dopaminergic neuronal markers. ResultsWe detected a significant decrease in Syn in the glomerular layer (GL) of OB and in the PFC of the AR group. Additionally, the optical density of GAD67 and VGLUT2 was reduced in the OB, AON and PFC, compared to controls. The behavioral tests demonstrated olfactory dysfunction and reduced male aggressiveness in AR rats, but we did not find any difference in the cognition and anxiety-like behavior. ConclusionsWe confirmed olfactory dysfunction in a rat model of AR and we identified modifications in synaptic activity by reduction of Syn optical density in the GL of the OB and in the PFC. This was accompanied by structural changes in glutamatergic and GABAergic activity in essential components of the olfactory pathway and PFC.

1. Previous studies in vivo and in vitro have shown that kindling from several locations in the limbic system induces the onset of epileptiform activity in the piriform (olfactory) cortex in the rat. In the present study we tested the hypothesis that kindled epileptiform events in piriform cortex are initiated in the underlying endopiriform nucleus. The experiments were performed in slices taken from rats that were previously kindled by conventional means. 2. Both stimulus-evoked and spontaneous interictal-like epileptiform events were observed in most slices from the anterior piriform cortex, but in few slices from the posterior piriform cortex. These events resembled those described in unanesthetized and urethan-anesthetized rats in previous studies. 3. Findings in support of the hypothesis were as follows. Epileptiform events in the endopiriform nucleus preceded those in the piriform cortex. Epileptiform events could occur in endopiriform nucleus alone, but were only observed in the piriform cortex following occurrence in the endopiriform nucleus. A buildup in population activity preceded the onset of all-or-none epileptiform events in the endopiriform nucleus. Epileptiform events could be triggered by local application of glutamate in the endopiriform nucleus and adjacent claustrum, but not from the piriform cortex. Finally, local application of Co2+ in the endopiriform nucleus, but not in the piriform cortex or elsewhere in the slices, blocked the occurrence of epileptiform events. 4. Additional experiments were performed to further characterize the generation process. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) blocked epileptiform events and the preceding accelerating buildup in multiunit activity at a concentration below that required to block the monosynaptic excitatory postsynaptic potential (EPSP). This suggests that EPSPs mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors underlie epileptiform events in slices of piriform cortex, and that multisynaptic interactions within the endopiriform nucleus are required for generation of these epileptiform EPSPs. By contrast, block of N-methyl-D-aspartate (NMDA) receptors decreased the amplitude of epileptiform EPSPs but did not block their occurrence, indicating that NMDA receptors contribute to generation but are not required. When membrane potential was depolarized to increase driving force, fast inhibitory postsynaptic potentials were found to consistently accompany the buildup process and epileptiform EPSPs. This indicates that if initiation of epileptiform activity in the endopiriform nucleus results from a compromise in feedback inhibition, this compromise is partial rather than complete. 5. Epileptiform EPSPs in slices of piriform cortex from kindled rats displayed similarities in properties, locus of origin, and mechanism of generation to those previously studied in slices from normal rats in which epileptiform activity was induced by a brief period of bursting activity. These similarities suggest that study of bursting-induced epileptiform EPSPs may provide insight into certain aspects of kindling-induced epileptogenesis.

Olfactory Predictive Codes and Stimulus Templates in Piriform Cortex

Recruitment of interictal- and ictal-like discharges in posterior piriform cortex by delta-rate (1–4 Hz) focal bursts in anterior piriform cortex in vivo

1. We investigated the development of epileptic activity in the limbic lobe of the in vitro isolated brain preparation after induction of a restricted epileptic focus in the rostral portion of the anterior piriform cortex (APC) by means of local bicuculline ejection. 2. The modifications of the local responses evoked by stimulation of the lateral olfactory tract were consistent with an increase in excitability of layer II pyramidal neurons. The abnormal discharge output of the epileptic focus propagated throughout the piriform cortex (PC) and generated late synaptic stimulus-evoked epileptiform potentials in layer Ib, where corticocortical associative fibers contact the distal dendrites of pyramidal cells. 3. Spontaneous epileptiform potentials (SEPs) originated in the primary focus at the bicuculline ejection site 10-15 min after drug application and propagated via associative fibers to the posterior PC (PPC). 4. Autonomous secondary foci generating SEPs independently from the primary anterior focus developed in the PPC within 2 h after the bicuculline application. 5. Ictal events seldom occurred spontaneously in PC but could be induced by tetanic afferent stimulation. Evoked ictal events in PC had the characteristics of afterdischarges, being short in duration and localized in space and showing a progressively decreasing firing rate. 6. Self-sustained spontaneous ictal discharges were observed in the entorhinal cortex and hippocampus but not in PC after activation of the APC focus. 7. We conclude that in an acute pharmacological model of focal epilepsy, associative corticocortical connections hold a primary role 1) in the propagation of interictal epileptiform activity throughout the limbic lobe and 2) in the generation of secondary epileptic foci. We also demonstrate that self-sustained ictal events are not spontaneously generated in PC, although paroxysmal seizure-like discharges occur in hippocampus. We discuss the relevance of the rostral-to-caudal-directed associative fiber system in generation of limbic seizures.

A hunger for odour: Leptin modulation of olfaction.

Patients with acquired, idiopathic olfactory dysfunction (OD) commonly undergo magnetic resonance imaging (MRI) evaluation to rule out intracranial pathologies. This practice is highly debated given the expense of MRI relative to the probability of detecting a treatable lesion. This, combined with the increasing use of MRI in research to investigate the mechanisms underlying OD, provided the impetus for this comprehensive review. The purpose of this systematic review was to both assess the utility of MRI in diagnosis of idiopathic OD and to describe MRI findings among mixed OD etiologies to better understand its role as a research tool in this patient population. A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies with original MRI data for patients with OD was completed. Studies exclusively investigating patients with neurocognitive deficits or those studying traumatic or congenital etiologies of OD were excluded. From 1758 candidate articles, 33 studies were included. Four studies reviewed patients with idiopathic OD for structural pathologies on MRI, of which 17 of 372 (4.6%) patients had a potential central cause identified, and 3 (0.8%) had an olfactory meningioma or olfactory neuroblastoma. Fourteen studies (42.4%) reported significant correlation between olfactory bulb volume and olfactory outcomes, and 6 studies (18.8%) reported gray matter volume reduction, specifically in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal, and piriform cortex areas, in patients with mixed OD etiologies. Functional MRI studies reported reduced brain activation and functional connectivity in olfactory network areas. MRI uncommonly detects intracranial pathology in patients with idiopathic OD. Among patients with mixed OD etiologies, reduced olfactory bulb and gray matter volume are the most common abnormal findings on MRI. Further research is required to better understand the role of MRI and its cost-effectiveness in patients with acquired, idiopathic OD.

Computational analyses of in-vivo cerebral activity show that gamma oscillations in the olfactory cortex originate from local feedback inhibition following each sniff and serve to segregate competing odor representations through a winner-take-all process, providing an optimal window to decode odor.

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Objective Using olfactory task functional magnetic resonance imaging (fMRI) to investigate the difference in brain olfactory activation between patients with subjective cognitive decline and normal elderly subjects, and to explore the objective image markers for early identification and evaluation the progression from SCD to Alzheimer′s disease (AD). Methods Twenty patients with SCD (SCD group) and twenty matched normal elderly subjects (NC group) were recruited from the community from March 2017 to December 2018. A full neuropsychological scale tests battery, olfactory behavioral tests and olfactory task-fMRI were performed. The differences between olfactory behavior, neuropsychological scales, and task-fMRI brain activation between the two groups were tested. Further, brain regions, which had significantly different activations under task-fMRI, were used as seeds for resting state functional connectivity (FC) analysis. Finally, the correlations between brain activation and olfactory behavior along with clinical neuropsychological scale tests were examined. Results The results of this study showed SCD had a significant decrease in olfactory behavior (olfactory recognition ability) compared with NC (t=-3.042, P<0.01), and there was no statistically significant difference in olfactory threshold. Significant declines were also observed in the SCD self-rating scale (t=6.973, P<0.01), the immediate (t=-4.623, P<0.01) and delayed (t=-2.746, P<0.01) testing of Philadelphia word learning, while the remaining neuropsychological scales were normal. In the olfactory task-fMRI, activation of bilateral primary olfactory cortical regions was significantly reduced in SCD patients, including bilateral entorhinal cortex, amygdala, piriform cortex, anterior olfactory nucleus, and head of the hippocampus. The resting state functional connectivity with the primary olfactory cortex (POC) as the seed showed that the functional connectivity between the olfactory system and the default model network (DMN) of SCD patients was significantly weakened (AlphaSim correction with voxel level P<0.01 and cluster level P<0.05). The Beta value of the left POC was significantly positively correlated with the olfactory threshold and Montreal cognitive assessment (MoCA) (r=0.329, P=0.041; r=0.317, P=0.046). Partial correlation analysis indicated that there was a significantly positive correlation between the FC of the left POC with the right/left inferior frontal gyrus, the left frontal middle gyrus and the right inferior parietal, and the score of immediate Philadelphia word learning test(r=0.411, P=0.008; r=0.400, P=0.011; r=0.329, P=0.003; r=0.454, P=0.003). The FC between the left POC and the right inferior temporal gyrus was negatively correlated with the score of trail making test (TMT) B, and the FC between the left POC and the right inferior was negatively correlated with score of language fluency test (r=-0.317, P=0.047; r=-0.333, P=0.036). The FC between the right POC and the left inferior parietal was positively correlated with the score of immediate Philadelphia word learning (r=0.315, P=0.048), while the FC between right POC and left middle occipital gyrus was negatively corrected with Language Fluency Test (r=-0.403, P=0.01). Conclusion Olfactory function has been impaired in SCD patients with normal standard cognition and phychiatric rating scales, and the changes in the activation of the primary olfactory cortex, such as the entorhinal cortex, may be an early neural circuit damage biomarker for objective evaluation of SCD. Key words: Subjective cognitive decline; Olfactory perception; Magnetic resonance imaging

The structure of the olfactory bulb and cortex of rats is described using the Timm method, in which endogenous transition or "heavy" metals are precipitated with sulfide and then stained with silver. With the light microscope, two types of staining, a fine, "colored" reaction and a coarse, "granular" reaction, are found in the neuropil of the adult forebrain; neuronal somata, fiber tracts, and some specific areas of the neuropil are almost unstained. With the electron microscope the Timm method consists of small silver granules, which are associated with axon terminals. These granules are located over the external surface of the presynaptic membrane, facing the synaptic cleft, and over synaptic vesicles, especially the internal surface of the vesicle membrane. This localization suggests that the reactive metals are related to a membrane component which is recycled during secretion of synaptic transmitters. The colored and granular reactions seen with the light microscope appear to be correlated with different intensities of staining of different types of axon terminals. The full extent of the olfactory cortex can be delineated by a bilaminar staining pattern in layer I, which coincides with the pattern of termination of fiber systems to the cortex demonstrated by axonal tracing experiments. The superficial part of layer I is very palely stained; this corresponds precisely to layer Ia, the zone of termination of fibers from the olfactory bulb. In contrast, the deep part of the layer is stained with an intense colored reaction; this corresponds precisely to layer Ib, the zone of termination of the major association fiber system within the olfactory cortex. A prominent granular reaction, which does not correspond to any known long axon system, is found in all layers of the cortex, although it is concentrated at the superficial edge of layer Ib and in layer II. Variations in staining in the several subdivisions of the olfactory cortex are illustrated and described. In the olfactory bulb, the most prominent staining is a relatively fine, granular reaction in the glomerular formations, which apparently corresponds to the olfactory nerve terminals. In immature rats, the Timm method stains the neuropil throughout the olfactory system, although the patterns and quality of staining differ from that found in adults. Before birth, the best-differentiated reaction is seen in glomeruli of the olfactory bulb and correlates well with the pattern of olfactory nerve ingrowth.(ABSTRACT TRUNCATED AT 400 WORDS)