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Adaptive regulation of feeding depends on linkage of internal states and food outcomes with contextual cues. Human brain imaging has identified dysregulation of a hippocampal-lateral hypothalamic area (LHA) network in binge eating, but mechanistic instantiation of underlying cell-types and circuitry is lacking. Here, we identify an evolutionary conserved and discrete Prodynorphin (Pdyn)-expressing subpopulation of Somatostatin (Sst)-expressing inhibitory neurons in the dorsolateral septum (DLS) that receives primarily dorsal, but not ventral, hippocampal inputs. DLS(Pdyn) neurons inhibit LHA GABAergic neurons and confer context- and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked effects seen with optogenetic silencing of DLS Pdyn INs, suggesting a potential role for DYNORPHIN-KAPPA OPIOID RECEPTOR signaling in contextual regulation of food-seeking. Together, our findings illustrate how the dorsal hippocampus has evolved to recruit an ancient LHA feeding circuit module through Pdyn DLS inhibitory neurons to link contextual information with regulation of food consumption.
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The selection and optimization of appropriate adaptive responses depends on interoceptive and exteroceptive stimuli as well as on the animal's ability to switch from one behavioral strategy to another. Although growing evidence indicate that dopamine D2R-mediated signaling events ensure the selection of the appropriate strategy for each specific situation, the underlying neural circuits through which they mediate these effects are poorly characterized. Here, we investigated the role of D2R signaling in a mesolimbic neuronal subpopulation expressing the Wolfram syndrome 1 (Wfs1) gene. This subpopulation is located within the nucleus accumbens, the central amygdala, the bed nucleus of the stria terminalis, and the tail of the striatum, all brain regions critical for the regulation of emotions and motivated behaviors. Using a mouse model carrying a temporally controlled deletion of D2R in WFS1-neurons, we demonstrate that intact D2R signaling in this neuronal population is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice. In addition, we found that reduced D2R signaling in WFS1-neurons impaired active avoidance learning and innate escape responses. Collectively, these findings identify a yet undocumented role for D2R signaling in WFS1-neurons as a novel effector through which dopamine optimizes appetitive behaviors and regulates defensive behaviors.
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Dopamina , Síndrome de Wolfram , Animales , Femenino , Masculino , Reacción de Prevención , Neuronas/fisiología , Receptores de Dopamina D1 , Receptores de Dopamina D2/genéticaRESUMEN
How does cognition regulate innate behaviors? While the cognitive functions of the cortex have been extensively studied, we know much less about how cognition can regulate innate motivated behaviors to fulfill physiological, safety and social needs. Selection of appropriate motivated behaviors depends on external stimuli and past experiences that helps to scale priorities. With its abundant inputs from neocortical and allocortical regions, the lateral septum (LS) is ideally positioned to integrate perception and experience signals in order to regulate the activity of hypothalamic and midbrain nuclei that control motivated behaviors. In addition, LS receives numerous subcortical modulatory inputs, which represent the animal internal states and also participate in this regulation. In this perspective, we argue that LS sub-circuits regulate distinct motivated behaviors by integrating neural activity from neocortical, allocortical and neuromodulatory inputs. In addition, we propose that lateral inhibition between LS sub-circuits may allow the emergence of functional units that orchestrates competing motivated behaviors.
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Hipotálamo , Neuronas , Animales , Neuronas/fisiología , Regulación hacia Abajo , Corteza CerebralRESUMEN
Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.
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Cognición , Fibronectinas/metabolismo , Hormonas/metabolismo , Condicionamiento Físico Animal , Animales , Conducta Animal , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Fibronectinas/genética , Eliminación de Gen , Expresión Génica , Ratones , Ratones Noqueados , FenotipoRESUMEN
Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone-which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans-regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. In the absence of systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, increased levels of corticosterone prolong HFSC quiescence and maintain hair follicles in an extended resting phase. Mechanistically, corticosterone acts on the dermal papillae to suppress the expression of Gas6, a gene that encodes the secreted factor growth arrest specific 6. Restoring Gas6 expression overcomes the stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity through its effect on the niche, and demonstrates that the removal of such inhibition drives HFSCs into frequent regeneration cycles, with no observable defects in the long-term.
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Corticosterona/farmacología , Folículo Piloso/citología , Células Madre/citología , Células Madre/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/cirugía , Adrenalectomía , Animales , División Celular/efectos de los fármacos , Femenino , Folículo Piloso/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Transcriptoma , Regulación hacia ArribaRESUMEN
Hippocampal circuitry is continuously modified by integration of adult-born dentate granule cells (DGCs). Prior work has shown that enhancing adult hippocampal neurogenesis decreases interference or overlap or conflict between ensembles of similar contexts and promotes discrimination of a shock-associated context from a similar, neutral context. However, the impact of enhanced integration of adult-born neurons on hippocampal network activity or downstream circuits such as the dorsolateral septum that mediate defensive behavioral responses is poorly understood. Here, we first replicated our finding that genetic expansion of the population of adult-born dentate granule cells (8 weeks and younger) promotes contextual fear discrimination. We found that enhanced contextual fear discrimination is associated with greater c-Fos expression in discrete hippocampal subfields along the proximo-distal and dorsoventral axis. Examination of the dorsolateral septum revealed an increase in activation of somatostatin expressing neurons consistent with recent characterization of these cells as calibrators of defensive behavior. Together, these findings begin to shed light on how genetically enhancing adult hippocampal neurogenesis affects activity of hippocampal-dorsolateral septal circuits.
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Región CA3 Hipocampal/fisiología , Giro Dentado/fisiología , Aprendizaje Discriminativo/fisiología , Miedo/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Tabique Pelúcido/fisiología , Somatostatina/metabolismo , Animales , Región CA3 Hipocampal/citología , Región CA3 Hipocampal/metabolismo , Giro Dentado/citología , Giro Dentado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos , Tabique Pelúcido/citología , Tabique Pelúcido/metabolismoRESUMEN
Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm, we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral septum (dCA3-DLS) projections in calibrating fear responses to certain and ambiguous contextual threats, respectively. Ventral CA3-DLS (vCA3-DLS) projections suppress fear responses in both certain and ambiguous contexts, whereas ventral CA3-CA1 (vCA3-vCA1) projections promote fear responses in both these contexts. Lastly, using retrograde monosynaptic tracing, ex vivo electrophysiological recordings, and optogenetics, we identify a sparse population of DLS parvalbumin (PV) neurons as putative relays of dCA3-DLS projections to diverse subcortical circuits. Taken together, these studies illuminate how distinct dCA3 and vCA3 outputs calibrate contextual fear discrimination.
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Región CA3 Hipocampal/fisiología , Miedo/fisiología , Hipocampo/fisiología , Vías Nerviosas/fisiología , Animales , Humanos , Masculino , RatonesRESUMEN
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.
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Región CA3 Hipocampal/fisiología , Giro Dentado/fisiología , Miedo/fisiología , Reacción Cataléptica de Congelación , Interneuronas/fisiología , Núcleos Septales/fisiología , Somatostatina/metabolismo , Adaptación Psicológica/fisiología , Animales , Ansiedad/fisiopatología , Condicionamiento Clásico , Discriminación en Psicología/fisiología , Interneuronas/metabolismo , Masculino , Ratones , Vías Nerviosas/fisiología , Optogenética , Núcleos Septales/metabolismoRESUMEN
Conditioned place preference (CPP) is widely used for evaluating the rewarding effects of drugs. Like other memories, CPP is proposed to undergo reconsolidation during which it is unstable and sensitive to pharmacological inhibition. Previous studies have shown that cocaine CPP can be apparently erased by extracellular signal-regulated kinase (ERK) pathway inhibition during cocaine reconditioning (re-exposure to the drug-paired environment in the presence of the drug). Here, we show that blockade of D1 receptors during reconditioning prevented ERK activation and induced a loss of CPP. However, we also unexpectedly observed a CPP disappearance in mice that underwent testing and reconditioning with cocaine alone, specifically in strong conditioning conditions. The loss was due to the intermediate test. CPP was not recovered with reconditioning or priming in the short term, but it spontaneously reappeared after a month. When we challenged the D1 antagonist-mediated erasure, we observed that both a high dose of cocaine and a first CPP test were required for this effect. Our results also suggest a balance between D1-dependent ERK pathway activation and an A2a-dependent mechanism in D2 striatal neurons in controlling CPP expression. Our data reveal that, paradoxically, a simple CPP test can induce a complete (but transient) loss of place preference following strong but not weak cocaine conditioning. This study emphasizes the complex nature of CPP memory and the importance of multiple parameters that must be taken into consideration when investigating reconsolidation.
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Cocaína/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Animales , Benzazepinas/farmacología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Técnica del Anticuerpo Fluorescente , Masculino , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , RecompensaRESUMEN
Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.
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Espinas Dendríticas/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Neuronas/metabolismo , Estrés Psicológico , Animales , Corticosterona/farmacología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Giro Dentado/metabolismo , Femenino , Silenciador del Gen , Hipocampo/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Ratones Transgénicos , Neuronas/patología , Factores SexualesRESUMEN
Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.
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Giro Dentado/citología , Generalización de la Respuesta , Memoria a Largo Plazo , Inhibición Neural , Envejecimiento/fisiología , Amígdala del Cerebelo/fisiología , Animales , Región CA3 Hipocampal/fisiología , Regulación hacia Abajo , Potenciales Postsinápticos Excitadores , Miedo , Femenino , Células HEK293 , Humanos , Interneuronas/fisiología , Proteínas con Dominio LIM/metabolismo , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismoRESUMEN
The original version of this Article contained an error in the spelling of the author Alexa H. Veenema, which was incorrectly given as Alexa Veenema. This has now been corrected in both the PDF and HTML versions of the Article.
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Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow-derived monocytes and macrophages are essential for structural and functional repair mechanisms, including regeneration of cerebral white matter and improvement in neurocognitive function. Using a granulocyte-colony stimulating factor (G-CSF) receptor knockout mouse model in combination with bone marrow cell transplantation, MRI, and neurocognitive functional assessments, we demonstrate that bone marrow-derived G-CSF-responsive cells home to the injured brain and are critical for altering neural progenitor cells and brain repair. Additionally, compared with untreated animals, animals that received G-CSF following radiation injury exhibited enhanced functional brain repair. Together, these results demonstrate that, in addition to its known role in defense and debris removal, the hematopoietic system provides critical regenerative drive to the brain that can be modulated by clinically available agents.
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Células de la Médula Ósea , Trasplante de Médula Ósea , Encéfalo/fisiología , Factor Estimulante de Colonias de Granulocitos/farmacología , Trastornos Neurocognitivos , Traumatismos Experimentales por Radiación , Regeneración/efectos de los fármacos , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/genética , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Noqueados , Monocitos/metabolismo , Monocitos/patología , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/fisiopatología , Trastornos Neurocognitivos/terapia , Traumatismos Experimentales por Radiación/genética , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/fisiopatología , Traumatismos Experimentales por Radiación/terapia , Regeneración/genética , Regeneración/efectos de la radiaciónRESUMEN
Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior dentate gyrus (aDG) and anterior CA2/CA3 (aCA2/CA3) of mice are necessary for discrimination of social, but not non-social, stimuli. Further, Oxtrs in aCA2/CA3 neurons recruit a population-based coding mechanism to mediate social stimuli discrimination. Optogenetic terminal-specific attenuation revealed a critical role for aCA2/CA3 outputs to posterior CA1 for discrimination of social stimuli. In contrast, aCA2/CA3 projections to aCA1 mediate discrimination of non-social stimuli. These studies identify a role for an aDG-CA2/CA3 axis of Oxtr expressing cells in discrimination of social stimuli and delineate a pathway relaying social memory computations in the anterior hippocampus to the posterior hippocampus to guide social recognition.
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Conducta Animal/fisiología , Discriminación en Psicología/fisiología , Hipocampo/fisiología , Receptores de Oxitocina/fisiología , Conducta Social , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Vías Nerviosas/fisiología , Neuronas/fisiología , OptogenéticaRESUMEN
The histone deacetylase SIRT6 promotes DNA repair, but its activity declines with age with a concomitant accumulation of DNA damage. Furthermore, SIRT6 knockout mice exhibit an accelerated aging phenotype and die prematurely. Here, we report that brain-specific SIRT6-deficient mice survive but present behavioral defects with major learning impairments by 4 months of age. Moreover, the brains of these mice show increased signs of DNA damage, cell death, and hyperphosphorylated Tau-a critical mark in several neurodegenerative diseases. Mechanistically, SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3α/ß. Finally, SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease. Taken together, our results suggest that SIRT6 is critical to maintain genomic stability in the brain and that its loss leads to toxic Tau stability and phosphorylation. Therefore, SIRT6 and its downstream signaling could be targeted in Alzheimer's disease and age-related neurodegeneration.
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Neuroprotección , Sirtuinas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Encéfalo/patología , Daño del ADN , Activación Enzimática , Eliminación de Gen , Inestabilidad Genómica , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Aprendizaje , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de Órganos , Fenotipo , Fosforilación , Estabilidad Proteica , Sirtuinas/deficiencia , Proteínas tau/metabolismoRESUMEN
The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)-CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal-cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD.
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Miedo/fisiología , Hipocampo/metabolismo , Neurogénesis/fisiología , Trastornos por Estrés Postraumático/metabolismo , Adulto , Animales , Miedo/psicología , Hipocampo/patología , Humanos , Red Nerviosa/metabolismo , Red Nerviosa/patología , Trastornos por Estrés Postraumático/patología , Trastornos por Estrés Postraumático/psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
The dentate gyrus (DG) of mammals harbors neural stem cells that generate new dentate granule cells (DGCs) throughout life. Behavioral studies using the contextual fear discrimination paradigm have found that selectively augmenting or blocking adult hippocampal neurogenesis enhances or impairs discrimination under conditions of high, but not low, interference suggestive of a role in pattern separation. Although contextual discrimination engages population-based coding mechanisms underlying pattern separation such as global remapping in the DG and CA3, how adult hippocampal neurogenesis modulates pattern separation in the DG is poorly understood. Here, we propose a role for adult-born DGCs in re-activation coupled modulation of sparseness through feed-back inhibition to govern global remapping in the DG.
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Addiction can be considered as a form of neuronal adaptation within the reward circuitry. Upon psychostimulant administration, long-term behavioral adaptations are associated with synaptic plasticity and morphological changes of medium spiny neurons (MSN) from the striatum. Increased spine density onto MSN in response to chronic cocaine exposure in mice has been described for more than a decade, but no evidence indicates that these newly formed spines establish connections. We developed a method for labeling, automated detection and morphological analysis of synaptic contacts. Individual labeling of neurons in mice that express the Vesicular GLUtamate Transporter-1 fused to Venus allows visualization of both dendritic spines and axonal boutons. Automated three-dimensional segmentation and morphometric analysis retrieve information on thousands of synapses at high resolution. We used this method to demonstrate that new cortico-striatal connections are formed in the striatum upon chronic cocaine. We also show that the cortical input weight is preserved over other cerebral inputs and that the newly formed spines contact pre-existing axonal boutons. Our results pave the way for other studies, since our method can be applied to any other neuronal type as demonstrated herein for glutamatergic connections on pyramidal neurons and Purkinje cells.