Olfactory Circuitry Research Articles

A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila

Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species—the olfactory circuitry of the fruit fly Drosophila melanogaster—provides an opportunity to explore circuit functions using genetic manipulations, which, along with high-resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure–function details of the presented mechanism of perception.

Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb.

Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates.

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.

Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

A Distinct Population of Microglia Supports Adult Neurogenesis in the Subventricular Zone.

Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural circuitry sculpture. Here, we addressed microglial functions in the subventricular zone (SVZ), the major postnatal neurogenic niche. Our results depict microglia as a conspicuous component of SVZ and its anterior extension, the rostral migratory stream, a pathway used by neuroblasts during their transit toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal progenitor survival and migration in the mammalian brain.

Molecular evidence for decreased synaptic efficacy in the postmortem olfactory bulb of individuals with schizophrenia

Multiple lines of evidence suggest altered synaptic plasticity/connectivity as a pathophysiologic mechanism for various symptom domains of schizophrenia. Olfactory dysfunction, an endophenotype of schizophrenia, reflects altered activity of the olfactory circuitry, which conveys signals from olfactory receptor neurons to the olfactory cortex via synaptic connections in the glomeruli of the olfactory bulb. The olfactory system begins with intranasal olfactory receptor neuron axons synapsing with mitral and tufted cells in the glomeruli of the olfactory bulb, which then convey signals directly to the olfactory cortex. We hypothesized that olfactory dysfunction in schizophrenia is associated with dysregulation of synaptic efficacy in the glomeruli of the olfactory bulb. To test this, we employed semi-quantitative immunohistochemistry to examine the olfactory bulbs of 13 postmortem samples from schizophrenia and their matched control pairs for glomerular expression of 5 pre- and postsynaptic proteins that are involved in the integrity and function of synapses. In the glomeruli of schizophrenia cases compared to their matched controls, we found significant decreases in three presynaptic proteins which play crucial roles in vesicular glutamate transport — synapsin IIa (−18.05%, p=0.019), synaptophysin (−24.08% p=0.0016) and SNAP-25 (−23.9%, p=0.046). Two postsynaptic proteins important for spine formation and glutamatergic signaling were also decreased—spinophilin (−17.40%, p=0.042) and PSD-95 (−34.06%, p=0.015). These findings provide molecular evidence for decreased efficacy of synapses within the olfactory bulb, which may represent a synaptic mechanism underlying olfactory dysfunction in schizophrenia.

BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo

Olfactory bulb granule cells (GCs) are axon-less, inhibitory interneurons that regulate the activity of the excitatory output neurons, the mitral and tufted cells, through reciprocal dendrodendritic synapses located on GC spines. These contacts are established in the distal apical dendritic compartment, while GC basal dendrites and more proximal apical segments bear spines that receive glutamatergic inputs from the olfactory cortices. This synaptic connectivity is vital to olfactory circuit function and is remodeled during development, and in response to changes in sensory activity and lifelong GC neurogenesis. Manipulations that alter levels of the neurotrophin brain-derived neurotrophic factor (BDNF) in vivo have significant effects on dendritic spine morphology, maintenance and activity-dependent plasticity for a variety of CNS neurons, yet little is known regarding BDNF effects on bulb GC spine maturation or maintenance. Here we show that, in vivo, sustained bulbar over-expression of BDNF in transgenic mice produces a marked increase in GC spine density that includes an increase in mature spines on their apical dendrites. Morphometric analysis demonstrated that changes in spine density were most notable in the distal and proximal apical domains, indicating that multiple excitatory inputs are potentially modified by BDNF. Our results indicate that increased levels of endogenous BDNF can promote the maturation and/or maintenance of dendritic spines on GCs, suggesting a role for this factor in modulating GC functional connectivity within adult olfactory circuitry.

Laminar specific detection of APP induced neurodegeneration and recovery using MEMRI in an olfactory based Alzheimer's disease mouse model

Manganese enhanced MRI (MEMRI) was used to detect specific laminar changes in the olfactory bulb (OB) to follow the progression of amyloid precursor protein (APP)-induced neuronal pathology and its recovery in a reversible olfactory based Alzheimer's disease (AD) mouse model. Olfactory dysfunction is an early symptom of AD, which suggests that olfactory sensory neurons (OSNs) may be more sensitive to AD related factors than neurons in other brain areas. Previously a transgenic mouse model was established that causes degeneration of OSNs by overexpressing humanized APP (hAPP), which results in a disruption of the olfactory circuitry with changes in the glomerular structure. In the present work, OB volume and manganese enhancement of the glomerular layer in the OB were decreased in mutant mice. Turning off APP overexpression with doxycycline produced a significant increase in manganese enhancement of the glomerular layer after only 1week, and further recovery after 3weeks, while treatment with Aβ antibody produced modest improvement with MRI measurements. Thus, MEMRI enables a direct tracking of laminar specific neurodegeneration through a non-invasive in vivo measurement. The use of MRI will enable assessment of the ability of different pharmacological reagents to block olfactory neuronal loss and can serve as a unique in vivo screening tool to both identify potential therapeutics and test their efficacy.

Olfactory bulb coding of odors, mixtures and sniffs is a linear sum of odor time profiles.

The olfactory system receives intermittent and fluctuating inputs arising from dispersion of odor plumes and active sampling by the animal. Previous work has suggested that the olfactory transduction machinery and excitatory-inhibitory olfactory bulb circuitry generate nonlinear population trajectories of neuronal activity that differ across odorants. Here we show that individual mitral/tufted (M/T) cells sum inputs linearly across odors and time. By decoupling odor sampling from respiration in anesthetized rats, we show that M/T cell responses to arbitrary odor waveforms and mixtures are well described by odor-specific impulse responses convolved with the odorant's temporal profile. The same impulse responses convolved with the respiratory airflow predict the classical respiration-locked firing of olfactory bulb neurons and several other reported response properties of M/T cells. These results show that the olfactory bulb linearly processes fluctuating odor inputs, thereby simplifying downstream decoding of stimulus identity and temporal dynamics.

A lateralized odor learning model in neonatal rats for dissecting neural circuitry underpinning memory formation.

Rat pups during a critical postnatal period (≤ 10 days) readily form a preference for an odor that is associated with stimuli mimicking maternal care. Such a preference memory can last from hours, to days, even life-long, depending on training parameters. Early odor preference learning provides us with a model in which the critical changes for a natural form of learning occur in the olfactory circuitry. An additional feature that makes it a powerful tool for the analysis of memory processes is that early odor preference learning can be lateralized via single naris occlusion within the critical period. This is due to the lack of mature anterior commissural connections of the olfactory hemispheres at this early age. This work outlines behavioral protocols for lateralized odor learning using nose plugs. Acute, reversible naris occlusion minimizes tissue and neuronal damages associated with long-term occlusion and more aggressive methods such as cauterization. The lateralized odor learning model permits within-animal comparison, therefore greatly reducing variance compared to between-animal designs. This method has been used successfully to probe the circuit changes in the olfactory system produced by training. Future directions include exploring molecular underpinnings of odor memory using this lateralized learning model; and correlating physiological change with memory strength and durations.

Thrombospondin 4 deficiency in mouse impairs neuronal migration in the early postnatal and adult brain.

In the post-natal rodent brain, neuronal precursors originating from the sub-ventricular zone (SVZ) migrate over a long distance along the rostral migratory stream (RMS) to eventually integrate the olfactory bulb neuronal circuitry. In order to identify new genes specifically expressed in the RMS, we have screened the Allen Brain Atlas Database. We focused our attention on Thrombospondin 4 (Thbs4), one of the 5 members of the Thrombospondin family of large, multidomain, extracellular matrix proteins. In post-natal and adult brain Thbs4 mRNA and protein are specifically expressed in the neurogenic regions, including the SVZ and along the entire RMS. RMS cells expressing Thbs4 are GFAP (Glial Fibrillary Acidic Protein) positive astrocytes. Histological analysis in both wild-type and Thbs4 knock-out mice revealed no major abnormality in the general morphology of these neurogenic regions. Nevertheless, immunostaining for doublecortin demonstrates that in Thbs4-KO, migration of newly formed neurons along the RMS is somehow impaired, with several neurons migrating out of the RMS. This is further supported by a Bromodeoxyuridine-based in vivo approach showing a decrease in the number of newly born neuronal precursors reaching the olfactory bulb, while proliferation in the SVZ is not affected compared to wild-type, both in young animals (P15) and in adults (8 to 12 weeks of age). Corroborating this observation, the number of Parvalbumin- and Calbindin-immunoreactive interneurons in the olfactory bulb is also reduced in Thbs4-KO. Together, these observations support a role for the astrocyte-secreted protein Thbs4 in the migration of newly form neurons within the RMS to the olfactory bulb.

Shh-proteoglycan interactions regulate maturation of olfactory glomerular circuitry.

The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala)), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry.

Using the Olfactory System as an In Vivo Model To Study Traumatic Brain Injury and Repair

Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75(NTR), β-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration.

Peak shift in honey bee olfactory learning

If animals are trained with two similar stimuli such that one is rewarding (S+) and one punishing (S-), then following training animals show a greatest preference not for the S+, but for a novel stimulus that is slightly more different from the S- than the S+ is. This peak shift phenomenon has been widely reported for vertebrates and has recently been demonstrated for bumblebees and honey bees. To explore the nature of peak shift in invertebrates further, here we examined the properties of peak shift in honey bees trained in a free-flight olfactory learning assay. Hexanal and heptanol were mixed in different ratios to create a continuum of odour stimuli. Bees were trained to artificial flowers such that one odour mixture was rewarded with 2 molar sucrose (S+), and one punished with distasteful quinine (S-). After training, bees were given a non-rewarded preference test with five different mixtures of hexanal and heptanol. Following training bees' maximal preference was for an odour mixture slightly more distinct from the S- than the trained S+. This effect was not seen if bees were initially trained with two distinct odours, replicating the classic features of peak shift reported for vertebrates. We propose a conceptual model of how peak shift might occur in honey bees. We argue that peak shift does not require any higher level of processing than the known olfactory learning circuitry of the bee brain and suggest that peak shift is a very general feature of discrimination learning.

Olfactory Dysfunction in the Elderly: Basic Circuitry and Alterations with Normal Aging and Alzheimer's Disease.

Preclinical detection of Alzheimer disease is critical to determining at-risk individuals in order to improve patient and caregiver planning for their futures and to identify individuals likely to benefit from treatment as advances in therapeutics develop over time. Identification of olfactory dysfunction at the preclinical and early stages of the disease is a potentially useful method to accomplish these goals. We first review basic olfactory circuitry. We then evaluate the evidence of pathophysiological change in the olfactory processing pathways during aging and Alzheimer disease in both human and animal models. We also review olfactory behavioral studies during these processes in both types of models. In doing so, we suggest hypotheses about the localization and mechanisms of olfactory dysfunction and identify important avenues for future work.

MeCP2 is required for activity-dependent refinement of olfactory circuits

Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were used to produce physiological synaptic activity in gene-targeted mice in which specific olfactory circuits are visualized. Our results reveal defective postnatal refinement of olfactory circuits in Mecp2 knock out (KO) mice after sensory (odorant) stimulation. This failure in refinement was associated with deficits in the normal responses to odorants, including brain-derived neurotrophic factor (BDNF) production, as well as changes in adhesion molecules known to regulate axonal convergence. The defective refinement observed in Mecp2 KO mice was prevented by daily treatment with ampakine beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal stage might circumvent the detrimental effect of MeCP2 deficiency on circuitry maturation. The present results provide in vivo evidence in real time for the role of MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity.

The banana code—natural blend processing in the olfactory circuitry of Drosophila melanogaster

Odor information is predominantly perceived as complex odor blends. For Drosophila melanogaster one of the most attractive blends is emitted by an over-ripe banana. To analyze how the fly's olfactory system processes natural blends we combined the experimental advantages of gas chromatography and functional imaging (GC-I). In this way, natural banana compounds were presented successively to the fly antenna in close to natural occurring concentrations. This technique allowed us to identify the active odor components, use these compounds as stimuli and measure odor-induced Ca2+ signals in input and output neurons of the Drosophila antennal lobe (AL), the first olfactory neuropil. We demonstrate that mixture interactions of a natural blend are very rare and occur only at the AL output level resulting in a surprisingly linear blend representation. However, the information regarding single components is strongly modulated by the olfactory circuitry within the AL leading to a higher similarity between the representation of individual components and the banana blend. This observed modulation might tune the olfactory system in a way to distinctively categorize odor components and improve the detection of suitable food sources. Functional GC-I thus enables analysis of virtually any unknown natural odorant blend and its components in their relative occurring concentrations and allows characterization of neuronal responses of complete neural assemblies. This technique can be seen as a valuable complementary method to classical GC/electrophysiology techniques, and will be a highly useful tool in future investigations of insect-insect and insect-plant chemical interactions.

Investigation of Neurophysiological Changes during Olfactory Habituation in Drosophila melanogaster

Event Abstract Back to Event Investigation of Neurophysiological Changes during Olfactory Habituation in Drosophila melanogaster Isabell Twick1*, John A. Lee1 and Mani Ramaswami1, 2 1 Trinity College Dublin, Ireland 2 National Centre for Biological Science, India Brain systems filter irrelevant sensory information. Habituation to inconsequential stimuli allows salient stimuli to be selectively broadcasted to attentional, emotional, and learning systems. Individuals diagnosed with autism spectrum disorder are impaired in habituation processes. This defect could contribute causally to stimulus hypersensitivity and altered salience mapping. Despite its importance, habituation mechanisms are poorly understood. Both, humans and fruit flies show habituation to odour stimuli. As their olfactory systems are remarkably conserved, Drosophila melanogaster with its genetic tools and well-defined olfactory circuitry is ideal to reveal conserved mechanisms of olfactory habituation (Twick et al., 2014) . Genetic and behavioral experiments in the Ramaswami lab suggest that continuous exposure to an odorant results in enhanced inhibitory transmission onto projection neurons activated by the odorant (Das, et al., 2011; Ramaswami, 2014). However, this simple model for habituation still needs to be tested on the basis of neurophysiological observations and further experiments will be required to elucidate potential mechanisms. My aim is to test and elaborate this enhanced inhibition model through experiments, which directly assess neurophysiological changes that occur during olfactory habituation. I have established a calcium imaging protocol that allows me to study changes in neuronal activity in a living preparation. Using this protocol I have shown alterations in the spatio-temporal activation patterns of a range of olfactory neuronal types after continuous odour exposure. I will continue to address whether and how the neuromodulator dopamine suppresses neurophysiological changes associated with olfactory habituation as indicated by behavioral experiments. Acknowledgements We thank Ronald Calabrese for insightful discussions on neuronal dynamics and circuitries and his advice and help with our experimental set up. References Twick I, Lee JA, Ramaswami M (2014) "Chapter 1 - Olfactory Habituation in Drosophila-Odor Encoding and its Plasticity in the Antennal Lobe." in Progress in Brain Research: Odor Memory and Perception, eds E. Barkai and D. Wilson (New York, NY: Elsevier), 177–203. Das S, Sadanandappa MK, Dervan A, Larkin A, Lee JA, Sudhakaran IP, Priya R, Heidari R, Holohan EE, Pimentel A, Gandhi A, Ito K, Sanyal S, Wang JW, Rodrigues V, Ramaswami M (2011) Plasticity of local GABAergic interneurons drives olfactory habituation. Proc Natl Acad Sci USA 108:646–654. Ramaswami M (2014) Network Plasticity in Adaptive Filtering and Behavioral Habituation. Neuron 82:1216-1229. Keywords: habituation, Drosophila, antennal lobe, spatiotemporal code, Olfaction, calcium imaging, Olfactory Habituation, local interneurons Conference: Neuroscience Ireland Young Neuroscientists Symposium 2014 , Dublin, Ireland, 20 Sep - 20 Sep, 2014. Presentation Type: Poster Presentation Topic: Early Career Neuroscience Citation: Twick I, Lee JA and Ramaswami M (2014). Investigation of Neurophysiological Changes during Olfactory Habituation in Drosophila melanogaster. Front. Neurosci. Conference Abstract: Neuroscience Ireland Young Neuroscientists Symposium 2014 . doi: 10.3389/conf.fnins.2014.87.00042 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Sep 2014; Published Online: 19 Sep 2014. * Correspondence: Miss. Isabell Twick, Trinity College Dublin, Dublin, Ireland, twicki@tcd.ie Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Isabell Twick John A Lee Mani Ramaswami Google Isabell Twick John A Lee Mani Ramaswami Google Scholar Isabell Twick John A Lee Mani Ramaswami PubMed Isabell Twick John A Lee Mani Ramaswami Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neonatal olfactory bulbectomy enhances locomotor activity, exploratory behavior and binding of NMDA receptors in pre-pubertal rats

In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied the effect of nOBX on the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors during development. The behavioral effects of nOBX (postnatal day 7, PD7) were investigated in pre- (PD30) and post-pubertal (PD60) Wistar rats. NMDA receptor activity was measured with [125I]MK-801 in the brain regions associated with the olfactory circuitry. A significant increase in the novelty-induced locomotion was seen in the pre-pubertal nOBX rats. Although the locomotor effect was less marked than in pre-pubertal rats, the nOBX rats tested post-pubertally failed to habituate to the novel situation as quickly as the sham- and normal- controls. Pre-pubertally, the head-dipping behavior was enhanced in nOBX rats compared with sham-operated and normal controls, while normal exploratory behavior was observed between groups in adulthood. In contrast, social interaction was increased in post-pubertal animals that underwent nOBX. Both pre- and post-pubertal nOBX rats recovered olfaction. Interestingly, pre-pubertal rats showed a significant increase in the [125I]MK-801 binding in the piriform cortex, dorsal hippocampus, inner and outer layers of the frontal cortex and outer layer of the cingulate cortex. At post-pubertal age, no significant differences in [125I]MK-801 binding were observed between groups at any of the brain regions analyzed. These results suggest that nOBX produces pre-pubertal behavioral disturbances and NMDA receptor changes that are transitory with recovery of olfaction early in adulthood.

Balancing Survival: The Role of CTGF in Controlling Experience-Modulated Olfactory Circuitry

The subventricular zone (SVZ) continuously supplies new interneurons that incorporate into pre-existing olfactory bulb circuitry. Khodosevich etal. (2013) show that connective tissue growth factor (CTGF) regulates a multicellular signaling cascade determining the number of postnatally born inhibitory interneurons in odor-activated glomeruli.

Olfactory bulbectomy induces neuronal rearrangement in the entorhinal cortex in the rat

In humans, depression has been associated with disturbances in olfactory circuitry. Symptoms of depression can be mimicked in animals after olfactory bulbectomy (OBX). Animal models of depression-like behavior produce similar neuronal rearrangements in various brain regions as seen in patients affected by depression. We have recently observed that OBX produces neuronal hypotrophy in the piriform cortex (PirC) and CA1 hippocampus as well as decreased adult cell proliferation in the dentate gyrus (DG) of hippocampus. Thus we further evaluated the effects of OBX in neuronal arborization and spine density in brain regions involved in the control of circadian circle, emotion and memory processing such as the prefrontal cortex (PFC), nucleus accumbens (NAcc), infralimbic cortex (ILC), orbitolateral cortex (OLC) and entorhinal cortex (EC). Our present results show that along with severe behavioral deficits observed in these animals, OBX considerably decreased dendritic branching and the total dendritic length in the EC, a major interface of the hippocampus and neocortical regions. The remaining cortices and NAcc were not affected by OBX. Thus, we propose that the lack of input from the olfactory bulbs resulted in serial neuronal rearrangements in the PirC, EC, and hippocampus leading, at least partially, to behavioral deficits in emotion and memory processes.