Rediscovering a Forgotten Link: TSPO and RIM-BP1 in Appetite Regulation.

The translocator protein of 18 kDa (TSPO) and RIM binding protein 1 (RIM-BP1) are both heavily expressed in neurons at the olfactory bulb. These proteins have overlapping functional profiles and are both implicated in the development of obesity. Over 20 years ago, a yeast 2-hybrid experiment discovered that RIM-BP1 interacts with a peptide constructed from a fraction of the TSPO sequence. Considering these data, the authors predict that the interaction between RIM-BP1 and TSPO could alter the olfactory system's mediation of appetite. Despite the therapeutic potential of this interaction, it has never been confirmed if the full TSPO protein and RIM-BP1 interact. The interaction is instead often cited as physiologically irrelevant. This commentary revisits the forgotten interaction between TSPO and RIM-BP1, reviewing all relevant literature discussing their relationship. Contrary to common discourse that the RIM-BP1 and TSPO are potential binding partners, while the interaction may regulate many neurological functions, existing evidence suggests that the interaction would have a specific role in odor-guided appetite. Further research into the nutritional neuroscientific consequences of TSPO/RIM-BP1 interactions should therefore be conducted.

Mapping GABAergic projections that mediate feeding.

Neuroscience offers important insights into the pathogenesis and treatment of obesity by investigating neural circuits underpinning appetite and feeding. Gamma-aminobutyric acid (GABA), one of the most abundant neurotransmitters in the brain, and its associated receptors represent an array of pharmacologically targetable mediators of appetite signalling. Targeting the GABAergic system is therefore an increasingly investigated approach to obesity treatment. However, the many GABAergic projections that control feeding have yet to be collectively analysed. This review provides a comprehensive analysis of the relationship between GABAergic signalling and appetite by examining both foundational studies and the results of newly emerging chemogenetic/optogenetic experiments. A current snapshot of these efforts to map GABAergic projections influencing appetite is provided, and potential avenues for further investigation are provided.

Does neuroscience research change behaviour? A scoping review and case study in obesity neuroscience.

The language employed by researchers to define and discuss diseases can itself be a determinant of health. Despite this, the framing of diseases in medical research literature is largely unexplored. This scoping review examines a prevalent medical issue with social determinants influenced by the framing of its pathogenesis: obesity. Specifically, we compare the currently dominant framing of obesity as an addiction to food with the emerging frame of obesity developing from neuroinflammation. We triangulate both corpus linguistic and bibliometric analysis of the top 200 most engaging neuroscience journal articles discussing obesity that were published open access in the past 10 years. The constructed Neurobesity Corpus is available for public use. The scoping review analysis confirmed that neuroinflammation is an emerging way for obesity to be framed in medical research. Importantly, the articles analysed that discussed neuroinflammation were less likely to use crisis terminology, such as referring to an obesity "epidemic". We highlight a potential relationship between the adoption of addiction frames and the use of stigmatising language in medical research.

The limitations of investigating appetite through circuit manipulations: are we biting off more than we can chew?

Disordered eating can underpin a number of debilitating and prevalent chronic diseases, such as obesity. Broader advances in psychopharmacology and biology have motivated some neuroscientists to address diet-induced obesity through reductionist, pre-clinical eating investigations on the rodent brain. Specifically, chemogenetic and optogenetic methods developed in the 21st century allow neuroscientists to perform in vivo, region-specific/projection-specific/promoter-specific circuit manipulations and immediately assess the impact of these manipulations on rodent feeding. These studies are able to rigorously conclude whether a specific neuronal population regulates feeding behaviour in the hope of eventually developing a mechanistic neuroanatomical map of appetite regulation. However, an artificially stimulated/inhibited rodent neuronal population that changes feeding behaviour does not necessarily represent a pharmacological target for treating eating disorders in humans. Chemogenetic/optogenetic findings must therefore be triangulated with the array of theories that contribute to our understanding of appetite. The objective of this review is to provide a wide-ranging discussion of the limitations of chemogenetic/optogenetic circuit manipulation experiments in rodents that are used to investigate appetite. Stepping into and outside of medical science epistemologies, this paper draws on philosophy of science, nutrition, addiction biology and neurophilosophy to prompt more integrative, transdisciplinary interpretations of chemogenetic/optogenetic appetite data. Through discussing the various technical and epistemological limitations of these data, we provide both an overview of chemogenetics and optogenetics accessible to non-neuroscientist obesity researchers, as well as a resource for neuroscientists to expand the number of lenses through which they interpret their circuit manipulation findings.

Retrieval of olfactory fear memory alters cell proliferation and expression of pCREB and pMAPK in the corticomedial amygdala and piriform cortex.

The brain forms robust associations between odors and emotionally salient memories, making odors especially effective at triggering fearful or traumatic memories. Using Pavlovian olfactory fear conditioning (OFC), a variant of the traditional tone-shock paradigm, this study explored the changes involved in its processing. We assessed the expression of neuronal plasticity markers phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB) and phosphorylated mitogen-activated protein kinase (pMAPK) 24 h and 14 days following OFC, in newborn neurons (EdU+) and in brain regions associated with olfactory memory processing; the olfactory bulb, piriform cortex, amygdale, and hippocampus. Here, we show that all proliferating neurons in the dentate gyrus of the hippocampus and glomerular layer of the olfactory bulb were colocalized with pCREB at 24 h and 14 days post-conditioning, and the number of proliferating neurons at both time points were statistically similar. This suggests the occurrence of long-term potentiation within the neurons of this pathway. Finally, OFC significantly increased the density of pCREB- and pMAPK-positive immunoreactive neurons in the medial and cortical subnuclei of the amygdala and the posterior piriform cortex, suggesting their key involvement in its processing. Together, our investigation identifies changes in neuroplasticity within critical neural circuits responsible for olfactory fear memory.

Dissecting the contribution of 5-HT1A auto- and heteroreceptors in sucrose overconsumption in mice.

The rise in obesity prevalence has been linked to overconsumption of high-sugar containing food and beverages. Recent evidence suggests that chronic sucrose consumption leads to changes in serotonergic neuroplasticity within the neural circuits involved in feeding control. Although there is a relationship between serotonin signalling in the brain and diet-induced obesity, the specific serotonin (5-HT) receptors or pathways involved remain unknown. The 5-HT1A receptor subtype plays a role in regulating mood, anxiety, and appetite, and has been associated with reversing addiction to substances of abuse. However, the respective role of 5-HT1A auto- vs heteroreceptors in sucrose consumption has not been examined. Mice were given controlled access to either 5%, 10% or 25% w/v sucrose, or water as a control, for 12 weeks using the well-established "drinking in the dark" protocol (n = 6-8 mice per group). Ligands selectively targeting 5-HT1A auto- and/or heteroreceptors (NLX-112, unbiased 5-HT1A receptor agonist; NLX-101, preferential heteroreceptor agonist; F13714, preferential autoreceptor agonist) were administered i.p. acutely after 6 and 12 weeks of sucrose consumption. The specific involvement of 5-HT1A receptors in these effects was verified by blockade with the selective 5-HT1A receptors antagonist WAY-100,635. The specific subpopulation of 5-HT1A receptors involved in sucrose consumption was dependent on the concentration of sucrose solution and the duration of exposure to sucrose (6 weeks vs 12 weeks). Long-term sucrose consumption leads to accentuated 5-HT1A autoreceptor function. Thus, targeting 5-HT1A autoreceptors might represent an effective therapeutic strategy to combat the rise in obesity resulting from the overconsumption of high-sugar diet.

Sucrose Consumption Alters Serotonin/Glutamate Co-localisation Within the Prefrontal Cortex and Hippocampus of Mice.

The overconsumption of sugar-sweetened food and beverages underpins the current rise in obesity rates. Sugar overconsumption induces maladaptive neuroplasticity to decrease dietary control. Although serotonin and glutamate co-localisation has been implicated in reward processing, it is still unknown how chronic sucrose consumption changes this transmission in regions associated with executive control over feeding-such as the prefrontal cortex (PFC) and dentate gyrus (DG) of the hippocampus. To address this, a total of 16 C57Bl6 mice received either 5% w/v sucrose or water as a control for 12 weeks using the Drinking-In-The-Dark paradigm (n = 8 mice per group). We then examined the effects of chronic sucrose consumption on the immunological distribution of serotonin (5-HT), vesicular glutamate transporter 3 (VGLUT3) and 5-HT+/VGLUT3+ co-localised axonal varicosities. Sucrose consumption over 12 weeks decreased the number of 5-HT-/VGLUT3+ and 5-HT+/VGLUT3+ varicosities within the PFC and DG. The number of 5-HT+/VGLUT3- varicosities remained unchanged within the PFC but decreased in the DG following sucrose consumption. Given that serotonin mediates DG neurogenesis through microglial migration, the number of microglia within the DG was also assessed in both experimental groups. Sucrose consumption decreased the number of DG microglia. Although the DG and PFC are associated with executive control over rewarding activities and emotional memory formation, we did not detect a subsequent change in DG neurogenesis or anxiety-like behaviour or depressive-like behaviour. Overall, these findings suggest that the chronic consumption of sugar alters serotonergic neuroplasticity within neural circuits responsible for feeding control. Although these alterations alone were not sufficient to induce changes in neurogenesis or behaviour, it is proposed that the sucrose consumption may predispose individuals to these cognitive deficits which ultimately promote further sugar intake.

Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner.

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

Long-Term Overconsumption of Sugar Starting at Adolescence Produces Persistent Hyperactivity and Neurocognitive Deficits in Adulthood.

Sugar has become embedded in modern food and beverages. This has led to overconsumption of sugar in children, adolescents, and adults, with more than 60 countries consuming more than four times (>100 g/person/day) the WHO recommendations (25 g/person/day). Recent evidence suggests that obesity and impulsivity from poor dietary habits leads to further overconsumption of processed food and beverages. The long-term effects on cognitive processes and hyperactivity from sugar overconsumption, beginning at adolescence are not known. Using a well-validated mouse model of sugar consumption, we found that long-term sugar consumption, at a level that significantly augments weight gain, elicits an abnormal hyperlocomotor response to novelty and alters both episodic and spatial memory. Our results are similar to those reported in attention deficit and hyperactivity disorders. The deficits in hippocampal-dependent learning and memory were accompanied by altered hippocampal neurogenesis, with an overall decrease in the proliferation and differentiation of newborn neurons within the dentate gyrus. This suggests that long-term overconsumption of sugar, as that which occurs in the Western Diet might contribute to an increased risk of developing persistent hyperactivity and neurocognitive deficits in adulthood.

Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder.

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF's effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF's essential involvement in alcohol's effect on neurogenesis. Overall, defining TNF's role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF's effects within the brain.

Pavlovian Olfactory Fear Conditioning: Its Neural Circuity and Importance for Understanding Clinical Fear-Based Disorders.

Odors have proven to be the most resilient trigger for memories of high emotional saliency. Fear associated olfactory memories pose a detrimental threat of potentially transforming into severe mental illness such as fear and anxiety-related disorders. Many studies have deliberated on auditory, visual and general contextual fear memory (CFC) processes; however, fewer studies have investigated mechanisms of olfactory fear memory. Evidence strongly suggests that the neuroanatomical representation of olfactory fear memory differs from that of auditory and visual fear memory. The aim of this review article is to revisit the literature regarding the understanding of the neurobiological process of fear conditioning and to illustrate the circuitry of olfactory fear memory.

Contextual Fear Conditioning Alter Microglia Number and Morphology in the Rat Dorsal Hippocampus.

Contextual fear conditioning is a Pavlovian conditioning paradigm capable of rapidly creating fear memories to contexts, such as rooms or chambers. Contextual fear conditioning protocols have long been utilized to evaluate how fear memories are consolidated, maintained, expressed, recalled, and extinguished within the brain. These studies have identified the lateral portion of the amygdala and the dorsal portion of the hippocampus as essential for contextual fear memory consolidation. The current study was designed to evaluate how two different contextual fear memories alter amygdala and hippocampus microglia, brain derived neurotrophic factor (BDNF), and phosphorylated cyclic-AMP response element binding (pCREB). We find rats provided with standard contextual fear conditioning to have more microglia and more cells expressing BDNF in the dentate gyrus as compared to a context only control group. Additionally, standard contextual fear conditioning altered microglia morphology to become amoeboid in shape - a common response to central nervous system insult, such as traumatic brain injury, infection, ischemia, and more. The unpaired fear conditioning procedure (whereby non-reinforced and non-overlapping auditory tones were provided at random intervals during conditioning), despite producing equivalent levels of fear as the standard procedure, did not alter microglia, BDNF or pCREB number in any dorsal hippocampus or lateral amygdala brain regions. Despite this, the unpaired fear conditioning protocol produced some alterations in microglia morphology, but less compared to rats provided with standard contextual fear conditioning. Results from this study demonstrate that contextual fear conditioning is capable of producing large alterations to dentate gyrus plasticity and microglia, whereas unpaired fear conditioning only produces minor changes to microglia morphology. These data show, for the first time, that Pavlovian fear conditioning protocols can induce similar responses as trauma, infection or other insults within the central nervous system.

Microtopography of fear memory consolidation and extinction retrieval within prefrontal cortex and amygdala.

RATIONALE: The precise neural circuitry that encodes fear memory and its extinction within the brain are not yet fully understood. Fearful memories can be persistent, resistant to extinction, and associated with psychiatric disorders, especially post-traumatic stress disorder (PTSD). Here, we investigated the microtopography of neurons activated during the recall of an extinguished fear memory, as well as the influence of time on this microtopography. METHODS: We used the plasticity-related phosphorylated mitogen-activated protein kinase (pMAPK) to identify neurons activated in the recall of consolidated and extinguished auditory Pavlovian fear memories in rats. Quantitatively matched brain regions were used to investigate activity in the amygdala and prefrontal cortex. RESULTS: Recall of a consolidated, nonextinguished auditory fear memory resulted in a significantly greater number of activated neurons located in the dorsolateral subdivision of the lateral amygdala (LADL) when recalled 24 h after consolidation but not when recalled 7 days later. We found that the recall of an extinction memory was associated with pMAPK activation in the ventrolateral subdivision of the lateral amygdala (LAVL). Next, we showed that the pattern of pMAPK expression in the prelimbic cortex differed spatially following temporal variation in the recall of that memory. The deep and superficial layers of the pre-limbic cortex were engaged in recent recall of a fear memory, but only the superficial layers were recruited if the recall occurred 7 days later. CONCLUSIONS: Collectively, our findings demonstrate a functional microtopography of auditory fear memory during consolidation and extinction at the microanatomical level within the lateral amygdala and medial prefrontal cortex.

Combined VEGF/PDGF improves olfactory regeneration after unilateral bulbectomy in mice.

The olfactory receptor neurons lining the nasal cavity have a remarkable capacity to regenerate throughout life. They are replenished continuously and their axons make new connections within the olfactory bulb. However, some factors such as head trauma and skull base surgery damage the olfactory nerve which lead to olfactory dysfunction. Losing the sense of smell has considerable effects on quality of life and life-expectancy. Therefore, there is a clear need to find a treatment for olfactory dysfunction. One such potential treatment is growth factor therapy which showed promising results in the spinal cord and brain injuries. The aim of the present study was to investigate whether combined delivery of two growth factors, vascular endothelial growth factor and platelet-derived growth factor treatment can improve the olfactory neurons regeneration in mice. The degeneration of the olfactory neurons was induced by unilateral bulbectomy. The treatment group received 1.5 µg of the combined growth factors intranasally, while the control injured group received saline. Growth factor treatment significantly increased the number of immature neurons at 5 and 7 days post injury and also the number of mature olfactory neurons at 10 and 14 days post bulbectomy. Regenerating axons extended over a larger volume in the operated cavity in the treatment group compared to control group at 14 days post bulbectomy. The growth factor treatment also significantly reduced astrocytic glia scar in the operated cavity. The results indicate that the combined delivery of the growth factors has the potential to improve olfactory dysfunction.

Factors that modulate olfactory dysfunction.

The olfactory system is one of a few areas in the nervous system which is capable of regeneration throughout the life. Olfactory sensory neurons reside in the nasal cavity are continuously replenished with new neurons arising from stem cells. Some factors such as aging, neurodegenerative diseases, head trauma, brain tumor extraction and infection cause olfactory dysfunction which significantly influences physical wellbeing, quality of life, mental health, nutritional status, memory processes, identifying danger and is associated with increased mortality. Therefore, finding a treatment to improve olfactory dysfunction is needed. Recent research efforts in the field have shown some very promising new approaches to treat olfactory dysfunction. This review explores the current studies that have addressed therapeutic approaches to improve olfactory neuron regeneration based on cell transplantation therapy, modulation of physiological olfactory dysfunction and drug treatments.

The Grueneberg olfactory organ neuroepithelium recovers after injury.

The Grueneberg organ (also termed Grueneberg ganglion) is an olfactory subsystem at the rostral nasal septum of rodents, and has been suggested to exist also in humans. Grueneberg organ neurons respond to coldness and alarm pheromones, but the anatomical arrangement and regenerative capacity are not fully characterised. We examined the relationship between the glia and the neurons using crosses of two transgenic mouse lines, S100ß-DsRed and OMP-ZsGreen, to visualise olfactory ensheathing cells (OECs) and Grueneberg olfactory neurons, respectively. Within the epithelium, Grueneberg organ OECs were in direct contact with Grueneberg organ neuron cell bodies. Individual axons from the neurons initially grew over the surface of the OECs before forming larger fascicles consisting of numerous axons and OECs. Considering the location of the Grueneberg organ so close to the external environment, it may be that the Grueneberg neurons are likely to be subject to damage suggesting that as in other olfactory regions there is a capacity for recovery after injury. Here, we used a well characterised model of olfactory nervous system injury, unilateral bulbectomy, to determine whether Grueneberg organ neurons degenerate after injury. We found that Grueneberg organ neurons degenerated in response to the axotomy, yet by 11 days post injury neurons and/or axons were detected again within the epithelium. Our results demonstrate that while Grueneberg organ neurons and glia have a distinct relationship in the epithelium, they have largely similar characteristics to that of the main olfactory neurons and glia.

Differing phagocytic capacities of accessory and main olfactory ensheathing cells and the implication for olfactory glia transplantation therapies.

The rodent olfactory systems comprise the main olfactory system for the detection of odours and the accessory olfactory system which detects pheromones. In both systems, olfactory axon fascicles are ensheathed by olfactory glia, termed olfactory ensheathing cells (OECs), which are crucial for the growth and maintenance of the olfactory nerve. The growth-promoting and phagocytic characteristics of OECs make them potential candidates for neural repair therapies such as transplantation to repair the injured spinal cord. However, transplanting mixed populations of glia with unknown properties may lead to variations in outcomes for neural repair. As the phagocytic capacity of the accessory OECs has not yet been determined, we compared the phagocytic capacity of accessory and main OECs in vivo and in vitro. In normal healthy animals, the accessory OECs accumulated considerably less axon debris than main OECs in vivo. Analysis of freshly dissected OECs showed that accessory OECs contained 20% less fluorescent axon debris than main OECs. However, when assayed in vitro with exogenous axon debris added to the culture, the accessory OECs phagocytosed almost 20% more debris than main OECs. After surgical removal of one olfactory bulb which induced the degradation of main and accessory olfactory sensory axons, the accessory OECs responded by phagocytosing the axon debris. We conclude that while accessory OECs have the capacity to phagocytose axon debris, there are distinct differences in their phagocytic capacity compared to main OECs. These distinct differences may be of importance when preparing OECs for neural transplant repair therapies.

Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system.

During development of the primary olfactory system, axon targeting is inaccurate and axons inappropriately project within the target layer or overproject into the deeper layers of the olfactory bulb. As a consequence there is considerable apoptosis of primary olfactory neurons during embryonic and postnatal development and axons of the degraded neurons need to be removed. Olfactory ensheathing cells (OECs) are the glia of the primary olfactory nerve and are known to phagocytose axon debris in the adult and postnatal animal. However, it is unclear when phagocytosis by OECs first commences. We investigated the onset of phagocytosis by OECs in the developing mouse olfactory system by utilizing two transgenic reporter lines: OMP-ZsGreen mice which express bright green fluorescent protein in primary olfactory neurons, and S100ß-DsRed mice which express red fluorescent protein in OECs. In crosses of these mice, the fate of the degraded axon debris is easily visualized. We found evidence of axon degradation at embryonic day (E)13.5. Phagocytosis of the primary olfactory axon debris by OECs was first detected at E14.5. Phagocytosis of axon debris continued into the postnatal animal during the period when there was extensive mistargeting of olfactory axons. Macrophages were often present in close proximity to OECs but they contributed only a minor role to clearing the axon debris, even after widespread degeneration of olfactory neurons by unilateral bulbectomy and methimazole treatment. These results demonstrate that from early in embryonic development OECs are the primary phagocytic cells of the primary olfactory nerve.

Radial glia phagocytose axonal debris from degenerating overextending axons in the developing olfactory bulb.

Axon targeting during the development of the olfactory system is not always accurate, and numerous axons overextend past the target layer into the deeper layers of the olfactory bulb. To date, the fate of the mis-targeted axons has not been determined. We hypothesized that following overextension, the axons degenerate, and cells within the deeper layers of the olfactory bulb phagocytose the axonal debris. We utilized a line of transgenic mice that expresses ZsGreen fluorescent protein in primary olfactory axons. We found that overextending axons closely followed the filaments of radial glia present in the olfactory bulb during embryonic development. Following overextension into deeper layers of the olfactory bulb, axons degenerated and radial glia responded by phagocytosing the resulting debris. We used in vitro analysis to confirm that the radial glia had phagocytosed debris from olfactory axons. We also investigated whether the fate of overextending axons was altered when the development of the olfactory bulb was perturbed. In mice that lacked Sox10, a transcription factor essential for normal olfactory bulb development, we observed a disruption to the morphology and positioning of radial glia and an accumulation of olfactory axon debris within the bulb. Our results demonstrate that during early development of the olfactory system, radial glia play an important role in removing overextended axons from the deeper layers of the olfactory bulb.

An acute growth factor treatment that preserves function after spinal cord contusion injury.

Inflammation of the spinal cord after traumatic spinal cord injury (SCI) leads to destruction of healthy tissue. This "secondary degeneration" is more damaging than the initial physical damage and is the major contributor to permanent loss of functions. In our previous study, we showed that combined delivery of two growth factors, vascular endothelial growth factor and platelet-derived growth factor, significantly reduced secondary degeneration after hemisection injury of the spinal cord in the rat. Growth factor treatment reduced the size of the lesion cavity at 30 days, compared to control animals, and further reduced the cavity at 90 days in treated animals, whereas in control animals the lesion cavity continued to increase in size. Growth factor treatment also reduced astrogliosis and reduced macroglia/macrophage activation around the injury site. Treatment with individual growth factors alone had similar effects to control treatments. The present study investigated whether growth factor treatment would improve locomotor behavior after spinal contusion injury, a more relevant pre-clinical model of SCI. The growth factors were delivered for the first 7 days to the injury site by osmotic minipump. Locomotor behavior was monitored at 1-28 days after injury using the Basso, Beattie and Bresnahan (BBB) score and at 30 days using automated gait analysis. Treated animals had BBB scores of 18; control animals scored 10. Treated animals had significantly reduced lesion cavities and reduced macroglia/macrophage activation around the injury site. We conclude that growth factor treatment preserved spinal cord tissues after contusion injury, thereby allowing functional recovery. This treatment has the potential to significantly reduce the severity of human spinal cord injuries.