Publications
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(2024) Current Biology. 34, 24, p. 5769-5773.e3 Abstract
The hippocampus forms unique neural representations for distinct experiences, supporting the formation of different memories.1,2,3,4,5,6 Hippocampal representations gradually change over time as animals repeatedly visit the same familiar environment (\u201crepresentational drift\u201d).7,8,9,10,11,12 Such drift has also been observed in other brain areas, such as the parietal,13,14 visual,15,16,17 auditory,18,19 and olfactory20 cortices. While the underlying mechanisms of representational drift remain unclear, a leading hypothesis suggests that it results from ongoing learning processes.20,21,22 According to this hypothesis, because the brain uses the same neural substrates to support multiple distinct representations, learning of novel stimuli or environments leads to changes in the neuronal representation of a familiar one. If this is true, we would expect drift in a given environment to increase following new experiences in other, unrelated environments (i.e., off-context experiences). To test this hypothesis, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly visited a familiar linear track over weeks. We introduced off-context experiences by placing mice in a novel environment for 1 h after each visit to the familiar track. Contrary to our expectations, these novel episodes decreased place cells representational drift. Our findings are consistent with a model in which representations of distinct memories occupy different areas within the neuronal activity space, and the drift of each of them within that space is constrained by the area occupied by the others.
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(2023) Neuron (Cambridge, Mass.). 111, 15, p. 2357-2366 Abstract
Hippocampal activity is critical for spatial memory. Within a fixed, familiar environment, hippocampal codes gradually change over timescales of days to weeks-a phenomenon known as representational drift. The passage of time and the amount of experience are two factors that profoundly affect memory. However, thus far, it has remained unclear to what extent these factors drive hippocampal representational drift. Here, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly explored two different familiar environments that they visited at different time intervals over weeks. We found that time and experience differentially affected distinct aspects of representational drift: the passage of time drove changes in neuronal activity rates, whereas experience drove changes in the cells' spatial tuning. Changes in spatial tuning were context specific and largely independent of changes in activity rates. Thus, our results suggest that representational drift is a multi-faceted process governed by distinct neuronal mechanisms.
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(2023) Cell Reports. 42, 2, 112119. Abstract
Hippocampal subfield CA3 is thought to stably store memories in assemblies of recurrently connected cells functioning as a collective. However, the collective hippocampal coding properties that are unique to CA3 and how such properties facilitate the stability or precision of the neural code remain unclear. Here, we performed large-scale Ca2+ imaging in hippocampal CA1 and CA3 of freely behaving mice that repeatedly explored the same, initially novel environments over weeks. CA3 place cells have more precise and more stable tuning and show a higher statistical dependence with their peers compared with CA1 place cells, uncovering a cell assembly organization in CA3. Surprisingly, although tuning precision and long-term stability are correlated, cells with stronger peer dependence exhibit higher stability but not higher precision. Overall, our results expose the three-way relationship between tuning precision, long-term stability, and peer dependence, suggesting that a cell assembly organization underlies long-term storage of information in the hippocampus.
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(2022) Cell reports (Cambridge). 41, 8, 111695. Abstract
Physical exercise is known to augment brain functioning, improving memory and cognition. However, while some of the physiological effects of physical activity on the brain are known, little is known about its effects on the neural code. Using calcium imaging in freely behaving mice, we study how voluntary exercise affects the quality and long-term stability of hippocampal place codes. We find that running accelerates the emergence of a more informative spatial code in novel environments and increases code stability over days and weeks. Paradoxically, although runners demonstrated an overall more stable place code than their sedentary peers, their place code changed faster when controlling for code quality level. A model-based simulation shows that the combination of improved code quality and faster representational drift in runners, but neither of these effects alone, could account for our results. Thus, exercise may enhance hippocampal function via a more informative and dynamic place code.
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(2022) Nature. 609, 7928, p. 772-778 Abstract
Astrocytic calcium dynamics has been implicated in the encoding of sensory information1-5, and modulation of calcium in astrocytes has been shown to affect behaviour6-10. However, longitudinal investigation of the real-time calcium activity of astrocytes in the hippocampus of awake mice is lacking. Here we used two-photon microscopy to chronically image CA1 astrocytes as mice ran in familiar or new virtual environments to obtain water rewards. We found that astrocytes exhibit persistent ramping activity towards the reward location in a familiar environment, but not in a new one. Shifting the reward location within a familiar environment also resulted in diminished ramping. After additional training, as the mice became familiar with the new context or new reward location, the ramping was re-established. Using linear decoders, we could predict the location of the mouse in a familiar environment from astrocyte activity alone. We could not do the same in a new environment, suggesting that the spatial modulation of astrocytic activity is experience dependent. Our results indicate that astrocytes can encode the expected reward location in spatial contexts, thereby extending their known computational abilities and their role in cognitive functions.
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(2022) Hippocampus. 32, 5, p. 359-372 Abstract
Neurons in the hippocampus fire in consistent sequence over the timescale of seconds during the delay period of some memory experiments. For longer timescales, the firing of hippocampal neurons also changes slowly over minutes within experimental sessions. It was thought that these slow dynamics are caused by stochastic drift or a continuous change in the representation of the episode, rather than consistent sequences unfolding over minutes. This paper studies the consistency of contextual drift in three chronic calcium imaging recordings from the hippocampus CA1 region in mice. Computational measures of consistency show reliable sequences within experimental trials at the scale of seconds as one would expect from time cells or place cells during the trial, as well as across experimental trials on the scale of minutes within a recording session. Consistent sequences in the hippocampus are observed over a wide range of time scales, from seconds to minutes. The hippocampal activity could reflect a scale-invariant spatiotemporal context as suggested by theories of memory from cognitive psychology.
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(2022) PLoS Computational Biology. 18, 2, e1009832. Abstract
Applying information theoretic measures to neuronal activity data enables the quantification of neuronal encoding quality. However, when the sample size is limited, a naïve estimation of the information content typically contains a systematic overestimation (upward bias), which may lead to misinterpretation of coding characteristics. This bias is exacerbated in Ca2+ imaging because of the temporal sparsity of elevated Ca2+ signals. Here, we introduce methods to correct for the bias in the naïve estimation of information content from limited sample sizes and temporally sparse neuronal activity. We demonstrate the higher accuracy of our methods over previous ones, when applied to Ca2+ imaging data recorded from the mouse hippocampus and primary visual cortex, as well as to simulated data with matching tuning properties and firing statistics. Our bias-correction methods allowed an accurate estimation of the information place cells carry about the animal's position (spatial information) and uncovered the spatial resolution of hippocampal coding. Furthermore, using our methods, we found that cells with higher peak firing rates carry higher spatial information per spike and exposed differences between distinct hippocampal subfields in the long-term evolution of the spatial code. These results could be masked by the bias when applying the commonly used naïve calculation of information content. Thus, a bias-free estimation of information content can uncover otherwise overlooked properties of the neural code.
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(2022) Cell reports (Cambridge). 38, 3, 110268. Abstract
Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimers disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.[Display omitted]CA1 firing rates are similar between WT and fAD model mice in active wakefulnessDown-regulation of CA1 firing rates by NREM sleep and anesthesia fails in fAD micefAD mutations impair stabilization of lower firing rate set points by anestheticsDHODH inhibition suppresses CA1 hyperexcitability under anesthesia in fAD miceZarhin et al. show that firing rate dyshomeostasis is masked during active wakefulness but surfaces during anesthesia and NREM sleep in hippocampal circuits, preceding global sleep and memory disturbances in a mouse model of familial Alzheimers disease.
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(2021) Current Biology. 31, 19, p. 4327-4339.e6 Abstract
Recent studies have shown that neuronal representations gradually change over time despite no changes in the stimulus, environment, or behavior. However, such representational drift has been assumed to be a property of high-level brain structures, whereas earlier circuits, such as sensory cortices, have been assumed to stably encode information over time. Here, we analyzed large-scale optical and electrophysiological recordings from six visual cortical areas in behaving mice that were repeatedly presented with the same natural movies. Contrary to the prevailing notion, we found representational drift over timescales spanning minutes to days across multiple visual areas, cortical layers, and cell types. Notably, neural-code stability did not reflect the hierarchy of information flow across areas. Although individual neurons showed time-dependent changes in their coding properties, the structure of the relationships between population activity patterns remained stable and stereotypic. Such population-level organization may underlie stable visual perception despite continuous changes in neuronal responses.
[Display omitted] The visual cortex exhibits representational drift over minutes to daysDrift is characterized by both changes in cells activity rates and tuningNeural-code stability does not follow the hierarchy of the visual systemThe relationships between population activity patterns remain stable over time
Deitch et al. find continuous changes in neuronal responses to the same stimuli (representational drift) over minutes to days across multiple visual areas, cortical layers, and cell types. Despite these changes in the coding of individual cells, the structure of the relationships between population activity patterns remains stable and stereotypic. -
(2020) Current Biology. 30, 8, p. 1467-1476 Abstract
Summary Hippocampal place cells selectively fire when an animal traverses a particular location and are considered a neural substrate of spatial memory. Place cells were shown to change their activity patterns (remap) across different spatial contexts but to maintain their spatial tuning in a fixed familiar context. Here, we show that mouse hippocampal neurons can globally remap, forming multiple distinct representations (maps) of the same familiar environment, without any apparent changes in sensory input or behavior. Alternations between maps occurred only across separate visits to the environment, implying switching between distinct stable attractors in the hippocampal network. Importantly, the different maps were spatially informative and persistent over weeks, demonstrating that they can be reliably stored and retrieved from long-term memory. Taken together, our results suggest that a memory of a given spatial context could be associated with multiple distinct neuronal representations, rather than just one.
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(2019) Nature Communications. 10, 1, 4745. Abstract
Measuring neuronal tuning curves has been instrumental for many discoveries in neuroscience but requires a priori assumptions regarding the identity of the encoded variables. We applied unsupervised learning to large-scale neuronal recordings in behaving mice from circuits involved in spatial cognition and uncovered a highly-organized internal structure of ensemble activity patterns. This emergent structure allowed defining for each neuron an 'internal tuning-curve' that characterizes its activity relative to the network activity, rather than relative to any predefined external variable, revealing place-tuning and head-direction tuning without relying on measurements of place or head-direction. Similar investigation in prefrontal cortex revealed schematic representations of distances and actions, and exposed a previously unknown variable, the 'trajectory-phase'. The internal structure was conserved across mice, allowing using one animal's data to decode another animal's behavior. Thus, the internal structure of neuronal activity itself enables reconstructing internal representations and discovering new behavioral variables hidden within a neural code.
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(2017) Cell Reports. 21, 4, p. 1102-1115 Abstract
Ca2+ imaging techniques permit time-lapse recordings of neuronal activity from large populations over weeks. However, without identifying the same neurons across imaging sessions (cell registration), longitudinal analysis of the neural code is restricted to population-level statistics. Accurate cell registration becomes challenging with increased numbers of cells, sessions, and inter-session intervals. Current cell registration practices, whether manual or automatic, do not quantitatively evaluate registration accuracy, possibly leading to data misinterpretation. We developed a probabilistic method that automatically registers cells across multiple sessions and estimates the registration confidence for each registered cell. Using large-scale Ca2+ imaging data recorded over weeks from the hippocampus and cortex of freely behaving mice, we show that our method performs more accurate registration than previously used routines, yielding estimated error rates
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(2015) eLife. 4, DECEMBER2015, 12247. Abstract
The capacity to remember temporal relationships between different events is essential to episodic memory, but little is currently known about its underlying mechanisms. We performed time-lapse imaging of thousands of neurons over weeks in the hippocampal CA1 of mice as they repeatedly visited two distinct environments. Longitudinal analysis exposed ongoing environmentindependent evolution of episodic representations, despite stable place field locations and constant remapping between the two environments. These dynamics time-stamped experienced events via neuronal ensembles that had cellular composition and activity patterns unique to specific points in time. Temporally close episodes shared a common timestamp regardless of the spatial context in which they occurred. Temporally remote episodes had distinct timestamps, even if they occurred within the same spatial context. Our results suggest that days-scale hippocampal ensemble dynamics could support the formation of a mental timeline in which experienced events could be mnemonically associated or dissociated based on their temporal distance.
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(2015) Current Opinion in Neurobiology. 32, p. 141-147 Abstract
Recording neuronal activity in behaving subjects has been instrumental in studying how information is represented and processed by the brain. Recent advances in optical imaging and bioengineering have converged to enable time-lapse, cell-type specific recordings of neuronal activities from large neuronal populations in deep-brain structures of freely behaving rodents. We will highlight these advancements, with an emphasis on miniaturized integrated microscopy for large-scale imaging in freely behaving mice. This technology potentially enables studies that were difficult to perform using previous generation imaging and current electrophysiological techniques. These studies include longitudinal and population-level analyses of neuronal representations associated with different types of naturalistic behaviors and cognitive or emotional processes.
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(2014) PLoS ONE. 9, 11, 112068. Abstract
Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal's state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (similar to 65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.
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(2013) Journal of Neuroscience. 33, 45, p. 17631-17640 Abstract
Understanding the neural correlates of behavior in the mammalian cortex requires measurements of activity in awake, behaving animals. Rodents have emerged as a powerful model for dissecting the cortical circuits underlying behavior attributable to the convergence of several methods. Genetically encoded calcium indicators combined with viral-mediated or transgenic tools enable chronic monitoring of calcium signals in neuronal populations and subcellular structures of identified cell types. Stable one- and two-photon imaging of neuronal activity in awake, behaving animals is now possible using new behavioral paradigms in head-fixed animals, or using novel miniature head-mounted microscopes in freely moving animals. This mini-symposium will highlight recent applications of these methods for studying sensorimotor integration, decision making, learning, and memory in cortical and subcortical brain areas. We will outline future prospects and challenges for identifying the neural underpinnings of task-dependent behavior using cellular imaging in rodents.
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(2013) Nature Neuroscience. 16, 3, p. 264-266 Abstract
Using Ca2+ imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the similar to 15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.
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(2011) Nature Methods. 8, 10, p. 871-878 Abstract
The light microscope is traditionally an instrument of substantial size and expense. Its miniaturized integration would enable many new applications based on mass-producible, tiny microscopes. Key prospective usages include brain imaging in behaving animals for relating cellular dynamics to animal behavior. Here we introduce a miniature (1.9 g) integrated fluorescence microscope made from mass-producible parts, including a semiconductor light source and sensor. This device enables high-speed cellular imaging across similar to 0.5 mm(2) areas in active mice. This capability allowed concurrent tracking of Ca2+ spiking in >200 Purkinje neurons across nine cerebellar microzones. During mouse locomotion, individual microzones exhibited large-scale, synchronized Ca2+ spiking. This is a mesoscopic neural dynamic missed by prior techniques for studying the brain at other length scales. Overall, the integrated microscope is a potentially transformative technology that permits distribution to many animals and enables diverse usages, such as portable diagnostics or microscope arrays for large-scale screens.
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(2011) Nature Medicine. 17, 2, p. 223228 Abstract
The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one-and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach, we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous and trauma-induced conditions.
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(2009) Biological Psychiatry. 65, 4, p. 283-288 Abstract
Background: Depressive behavior in animals is often associated with reduced levels of brain-derived neurotrophic factor (BDNF) and impaired neurogenesis in the hippocampus. Recent studies showed that T cells recognizing central nervous system (CNS)-specific antigens can regulate adult hippocampal neurogenesis and expression of BDNF. On the basis of these findings, we hypothesized that controlling CNS specific immune activity by immunization with a myelin-related peptide may have an antidepressant effect. Methods: We investigated the impact of immunization with a CNS related peptide, on the behavioral and cellular outcomes of chronic mild stress (CMS; an animal model for depression) in rats. Results: Immunization with a weak agonist of a myelin-derived peptide ameliorated depressive behavior such as anhedonia (measured by sucrose preference), induced by CMS in rats. The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis. Conclusions: The results of this study introduce a novel approach of immunization with CNS-related antigens as a therapeutic means for fighting depression. Vaccination, as an antidepressant therapy, may invoke several molecular and cellular pathways that are known to be regulated by antidepressant drugs. Therefore, we suggest that immune-based therapies should be considered for treatment of depression.
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(2008) Trends in Molecular Medicine. 14, 11, p. 471-478 Abstract
Immune cells and immune molecules have recently been shown to support neurogenesis from neural stem and progenitor cells in the adult brain. This non-classical immune activity takes place constantly under normal physiological conditions and is extended under acute pathological conditions to include the attraction of progenitor cells and induction of neurogenesis in regions of the adult central nervous system (CNS) in which formation of new neurons does not normally occur. We suggest that the immune system should be viewed as a novel player in the adult neural stem cell niche and a coordinator of cell renewal processes after injury. We discuss these notions in light of the well-known facts that both immune-cell activity and cell renewal are inherently limited in the adult CNS and that immune and stem cells provide the body's mechanisms of repair.
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(2008) Rejuvenation Research. 11, 5, p. 903-913 Abstract
Aging is often associated with a decline in hippocampus-dependent spatial memory. Here, we show that functional cell-mediated immunity is required for the maintenance of hippocampus-dependent spatial memory. Sudden imposition of immune compromise in young mice caused spatial memory impairment, whereas immune reconstitution reversed memory deficit in immune-deficient mice. Analysis of hippocampal gene expression suggested that immune-dependent spatial memory performance was associated with the expression of insulin-like growth factor (Igf1) and of genes encoding proteins related to presynaptic activity (Syt10, Cplx2). We further showed that memory loss in aged mice could be attributed to age-related attenuation of the immune response and could be reversed by immune system activation. Homeostatic-driven proliferation of lymphocytes, which expands the existing T cell repertoire, restored spatial memory deficits in aged mice. Thus, our results identify a novel function of the immune system in the maintenance of spatial memory and suggest an original approach for arresting or reversing age-associated memory loss.
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(2008) Trends in Pharmacological Sciences. 29, 6, p. 287-293 Abstract
Mounting evidence from the last decade has shown that the immune system not only fights pathogens but also protects the body against cancer. More recently, immune surveillance has been shown to be important for maintaining the functional integrity of the central nervous system. The immune system, however, does not always prevail; tumors do grow and eventually kill their host, and devastating neurodegenerative conditions do develop. Neurodegenerative diseases, like tumors, lie dormant long before clinical symptoms appear. We propose that at this dormant stage, an ongoing competition between the local disease-causing factors and the immune system's attempts to contain them takes place. Onset of clinical symptoms occurs after disease-causing factors escape immune surveillance. Identifying the immune escape mechanisms and circumventing them soon after the emergence of clinical symptoms could lead to the development of novel therapeutic intervention for some of the most devastating neurodegenerative disorders.
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(2008) Trends in Immunology. 29, 5, p. 211-219 Abstract
Although there is a growing acceptance that immune cells could play a protective role under various injurious or pathological conditions of the central nervous system (CNS), the possibility that the immune system is constantly involved in day-to-day maintenance of CNS functional integrity has not been acknowledged. Here, we propose a unifying hypothesis, based on a recent collection of experimental results, suggesting that the loss of immunity to certain self-antigens or its insufficiency when encountering increased levels of risk factors is an important underlying factor in the onset or escalation of neurodegenerative processes, age-related dementia or mental dysfunction. We further suggest a model that explains how immunity to self exerts its roles in the special immune-privileged context of the CNS.
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(2008) Brain Behavior And Immunity. 22, 2, p. 167-176 Abstract
Neurogenesis, the formation of new neurons from stem/progenitor cells, occurs in the hippocampal dentate gyrus throughout life. Although the exact function of adult hippocampal neurogenesis is currently unknown, recent studies suggest that the newly formed neuronal population plays an important role in hippocampal-dependent cognitive abilities, including declarative memory. The process of adult neurogenesis is greatly influenced by the interaction between cells of the adaptive immune system and CNS-resident immune cells. Our laboratory has recently demonstrated that immune cells contribute to maintaining life-long hippocampal neurogenesis. The regulation of such immune-cell activity is crucial: too little immune activity (as in immune deficiency syndromes) or too much immune activity (as in severe inflammatory diseases) can lead to impaired hippocampal neurogenesis, which could then result in impaired hippocampal-dependent cognitive abilities. From these converging discoveries arise a mechanism that can explain one route by which our body affects our mind.
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(2007) Stem Cells. 25, 9, p. 2277-2282 Abstract
Neural stem/progenitor cells are known to exist in the intact spinal cord, but the presence of newly formed neurons during adulthood has not been documented there to date. Here, we report the appearance of newly formed neurons under normal physiological conditions. These neurons are immature, express a GABAergic phenotype, and are primarily located in the dorsal part of the spinal cord. This localization appeared to be mediated by stromal-derived factor-1/CXC-chemokine receptor-4 signaling in the dorsal region. The extent of spinal cord neurogenesis was found to be greatly influenced by immune system integrity and in particular by myelin-specific T cells. These observations provide evidence for in vivo spinal cord neurogenesis under nonpathological conditions and introduce novel mechanisms regulating adult spinal cord plasticity.
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(2007) Nature Cell Biology. 9, 9, p. 10811088 Abstract
Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCα/β-dependent activation of the NF-κB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.
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(2007) Stroke. 38, 2, p. 774-782 Abstract
The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy. (Stroke. 2007;38[part 2]:774-782.)
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(2006) Proceedings of the National Academy of Sciences of the United States of America. 103, 48, p. 18380 Abstract
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Immune cell-based regulation of adult neurogenesis(2006) p. 387-391 Abstract
Neurogenesis is known to continuously take place in certain neurogenic areas of the adult central nervous system (CNS) and can be induced in non-neurogenic areas under traumatic or degenerative conditions. Here we introduce T cells and CNS-resident microglia as important players in the regulation of adult neurogenesis. Under normal conditions, immune deficient mice (SCID and nude) and transgenic mice that most of their T-cell pool is specific for an irrelevant antigen (ovalbumin) exhibited impaired hippocampal neurogenesis. In contrast, mice in which the majority of T cells specifically recognize the CNSabundant antigen myelin basic protein showed normal neurogenesis. CNSspecific T cells were also found to be important for spatial learning abilities and for brain-derived neurotrophic factor expression in the dentate gyrus. Environmental enrichment did not evoke enhanced neurogenesis in immune-deficient animals, whereas in wild-type animals it led to enhanced hippocampal neurogenesis coupled with recruitment of T cells and activation of microglia. The clinical implications of these findings were tested using a rat model of cerebral ischemic insult. We demonstrate that Tcell based immune activation following stroke induces a robust elevation of neurogenesis in the hippocampus as well as in the cerebral cortex. Our results suggest that T cells, acting via resident antigen presenting cells, are important regulators of adult neurogenesis under both physiological and pathological conditions.
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(2006) Proceedings of the National Academy of Sciences of the United States of America. 103, 35, p. 13174-13179 Abstract
The well regulated activities of microglia and T cells specific to central nervous system (CNS) antigens can contribute to the protection of CNS neural cells and their renewal from adult neural stem/progenitor cells (aNPCs). Here we report that T cell-based vaccination of mice with a myelin-derived peptide, when combined with transplantation of aNPCs into the cerebrospinal fluid (CSF), synergistically promoted functional recovery after spinal cord injury. The synergistic effect was correlated with modulation of the nature and intensity of the local T cell and microglial response, expression of brain-derived neurotrophic factor and noggin protein, and appearance of newly formed neurons from endogenous precursor-cell pools. These results substantiate the contention that the local immune response plays a crucial role in recruitment of aNPCs to the lesion site, and suggest that similar immunological manipulations might also serve as a therapeutic means for controlled migration of stem/progenitor cells to other acutely injured CNS sites.
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(2006) Journal of Neurobiology. 66, 6, p. 552-563 Abstract
Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with selfantigens or on weakening of the activity of regulatory T cells.
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(2006) Journal of Clinical Investigation. 116, 4, p. 905-915 Abstract
The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-γ (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-α production, and overcame blockage of IGF-I production caused by IFN-γ. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool.
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(2006) Nature Neuroscience. 9, 2, p. 268-275 Abstract
Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.
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(2006) Molecular and Cellular Neuroscience. 31, 1, p. 149-160 Abstract
Cell renewal in the adult central nervous system (CNS) is limited, and is blocked in inflammatory brain conditions. We show that both neurogenesis and oligodendrogenesis of adult neural progenitor cells in mice are blocked by inflammation-associated (endotoxin-activated) microglia, but induced by microglia activated by cytokines (IL-4 or low level of IFN-γ) associated with T-helper cells. Blockage was correlated with up-regulation of microglial production of tumor necrosis factor-α. The effect induced by IL-4-activated microglia was mediated, at least in part, by insulin-like growth factor-I. The IL-4-activated microglia showed a bias towards oligodendrogenesis whereas the IFN-γ-activated microglia showed a bias towards neurogenesis. It thus appears that microglial phenotype critically affects their ability to support or impair cell renewal from adult stem cell.
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(2005) Proceedings of the National Academy of Sciences of the United States of America. 102, 39, p. 14122 Abstract
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(2004) Proceedings of the National Academy of Sciences of the United States of America. 101, 21, p. 8180-8185 Abstract
The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.
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(2002) Nature Genetics. 31, 4, p. 370-377 Abstract
Standard clustering methods can classify genes successfully when applied to relatively small data sets, but have limited use in the analysis of large-scale expression data, mainly owing to their assignment of a gene to a single cluster. Here we propose an alternative method for the global analysis of genome-wide expression data. Our approach assigns genes to context-dependent and potentially overlapping 'transcription modules', thus overcoming the main limitations of traditional clustering methods. We use our method to elucidate regulatory properties of cellular pathways and to characterize cis-regulatory elements. By applying our algorithm systematically to all of the available expression data on Saccharomyces cerevisiae, we identify a comprehensive set of overlapping transcriptional modules. Our results provide functional predictions for numerous genes, identify relations between modules and present a global view on the transcriptional network.