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1.
Dev Psychobiol ; 66(3): e22473, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38433422

RESUMEN

Evolutionarily conserved, peer-directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward-related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic "reward" circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. We previously demonstrated that during adolescence, in rats, microglial synaptic pruning shapes the development of NAc and social play behavior in males and females. In this report, we hypothesize that interrupting microglial pruning in NAc during adolescence will have persistent effects on male and female social behavior in adulthood. We found that inhibiting microglial pruning in the NAc during adolescence had different effects on social behavior in males and females. In males, inhibiting pruning increased familiar exploration and increased nonsocial contact. In females, inhibiting pruning did not change familiar exploration behavior but increased active social interaction. This leads us to infer that naturally occurring NAc pruning serves to reduce social behaviors toward a familiar conspecific in both males and females.


Asunto(s)
Encéfalo , Conducta Social , Adolescente , Humanos , Adulto , Femenino , Masculino , Animales , Ratas , Conducta Exploratoria , Interacción Social , Dopamina , Plasticidad Neuronal
2.
PLoS Comput Biol ; 18(2): e1009845, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35120128

RESUMEN

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.


Asunto(s)
Hipocampo/metabolismo , Receptores de Glutamato/metabolismo , Animales , Astrocitos/metabolismo , Ratones , Propiedades de Superficie
3.
J Neurosci ; 41(5): 947-959, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33298536

RESUMEN

Long-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences to guide future behavior. In the experimentally advantageous marine mollusk Aplysia, LTM for sensitization can be induced by the presentation of two aversive shocks to the animal's tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene apc/ebp mRNA, a prolonged increase in apc/ebp gene expression required for LTM formation requires the addition of TGFß signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of apc/ebp We find that this prolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the RNA-binding protein ApELAV. This interaction is promoted by p38 MAPK activation initiated by TGFß. We further demonstrate that blocking the interaction of ApELAV with its target mRNA during Trial 2 blocks both the prolonged increase in apc/ebp gene expression and the behavioral induction of LTM. Collectively, our findings elucidate both when and how ELAV proteins are recruited for the stabilization of mRNA in LTM formation. Stabilization of a transiently expressed immediate early gene mRNA by a repeated training trial may therefore serve as a "filter" for learning, permitting only specific events to cause lasting transcriptional changes and behavioral LTM.SIGNIFICANCE STATEMENT: In the present paper, we significantly extend the general field of molecular processing in long-term memory (LTM) by describing a novel form of pretranslational processing required for LTM, which relies on the stabilization of a newly synthesized mRNA by a class of RNA binding proteins (ELAVs). There are now compelling data showing that important processing can occur after transcription of a gene, but before translation of the message into protein. Although the potential importance of ELAV proteins in LTM formation has previously been reported, the specific actions of ELAV proteins during LTM formation remained to be understood. Our new findings thus complement and extend this literature by demonstrating when and how this post-transcriptional gene regulation is mediated in the induction of LTM.


Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteínas ELAV/metabolismo , Memoria a Largo Plazo/fisiología , ARN Mensajero/metabolismo , Animales , Aplysia , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteínas ELAV/genética , Memoria a Largo Plazo/efectos de los fármacos , Unión Proteica/fisiología , ARN Mensajero/genética , Factor de Crecimiento Transformador beta1/toxicidad
4.
Glia ; 69(4): 1061-1074, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33336855

RESUMEN

YAP and TAZ are effectors of the Hippo pathway that controls multicellular development by integrating chemical and mechanical signals. Peripheral nervous system development depends on the Hippo pathway. We previously showed that loss of YAP and TAZ impairs the development of peripheral nerve as well as Schwann cell myelination. The role of the Hippo pathway in peripheral nerve regeneration has just started to be explored. After injury, Schwann cells adopt new identities to promote regeneration by converting to a repair-promoting phenotype. While the reprogramming of Schwann cells to repair cells has been well characterized, the maintenance of such repair phenotype cannot be sustained for a very long period, which limits nerve repair in human. First, we show that short or long-term myelin maintenance is not affected by defect in YAP and TAZ expression. Using crush nerve injury and conditional mutagenesis in mice, we also show that YAP and TAZ are regulators of repair Schwann cell proliferation and differentiation. We found that YAP and TAZ are required in repair Schwann cells for their redifferentiation into myelinating Schwann cell following crush injury. In this present study, we describe how the Hippo pathway and YAP and TAZ regulate remyelination over time during peripheral nerve regeneration.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Vía de Señalización Hippo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular , Diferenciación Celular , Proliferación Celular , Ratones , Regeneración Nerviosa , Células de Schwann/metabolismo
5.
Neurobiol Learn Mem ; 125: 47-54, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26238564

RESUMEN

Cellular changes underlying memory formation can be generated in an activity-dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1h after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades at the synapses.


Asunto(s)
Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/fisiología , Sinapsis/metabolismo , Animales , Aplysia , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología
6.
Learn Mem ; 21(4): 199-204, 2014 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-24639486

RESUMEN

Mechanistically distinct forms of long-lasting plasticity and memory can be induced by a variety of different training patterns. Although several studies have identified distinct molecular pathways that are engaged during these different training patterns, relatively little work has explored potential interactions between pathways when they are simultaneously engaged in the same neurons and circuits during memory formation. Aplysia californica exhibits two forms of intermediate-term synaptic facilitation (ITF) in response to two different training patterns: (1) repeated trial (RT) ITF (induced by repeated tail nerve shocks [TNSs] or repeated serotonin [5HT] application) and (2) activity-dependent (AD) ITF (induced by sensory neuron activation paired with a single TNS or 5HT pulse). RT-ITF requires PKA activation and de novo protein synthesis, while AD-ITF requires PKC activation and has no requirement for protein synthesis. Here, we explored how these distinct molecular pathways underlying ITF interact when both training patterns occur in temporal register (an "Interactive" training pattern). We found that (1) RT, AD, and Interactive training all induce ITF; (2) Interactive ITF requires PKC activity but not de novo protein synthesis; and (3), surprisingly, Interactive training blocks persistent PKA activity 1 h after training, and this block is PKC-independent. These data support the hypothesis that sensory neuron activity coincident with the last RT training trial is sufficient to convert the molecular signaling already established by RT training into an AD-like molecular phenotype.


Asunto(s)
Plasticidad Neuronal/fisiología , Células Receptoras Sensoriales/fisiología , Transducción de Señal/fisiología , Transmisión Sináptica/fisiología , Animales , Aplysia , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Electrochoque , Biosíntesis de Proteínas , Proteína Quinasa C/metabolismo , Serotonina/metabolismo , Cola (estructura animal)
7.
Learn Mem ; 21(4): 215-22, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24639488

RESUMEN

Neurotrophins are critically involved in developmental processes such as neuronal cell survival, growth, and differentiation, as well as in adult synaptic plasticity contributing to learning and memory. Our previous studies examining neurotrophins and memory formation in Aplysia showed that a TrkB ligand is required for MAPK activation, long-term synaptic facilitation (LTF), and long-term memory (LTM) for sensitization. These studies indicate that neurotrophin-like molecules in Aplysia can act as key elements in a functionally conserved TrkB signaling pathway. Here we report that we have cloned and characterized a novel neurotrophic factor, Aplysia cysteine-rich neurotrophic factor (apCRNF), which shares classical structural and functional characteristics with mammalian neurotrophins. We show that apCRNF (1) is highly enriched in the CNS, (2) enhances neurite elongation and branching, (3) interacts with mammalian TrkB and p75(NTR), (4) is released from Aplysia CNS in an activity-dependent fashion, (5) facilitates MAPK activation in a tyrosine kinase dependent manner in response to sensitizing stimuli, and (6) facilitates the induction of LTF. These results show that apCRNF is a native neurotrophic factor in Aplysia that can engage the molecular and synaptic mechanisms underlying memory formation.


Asunto(s)
Aplysia/fisiología , Potenciación a Largo Plazo/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Factores de Crecimiento Nervioso/metabolismo , Sinapsis/fisiología , Secuencia de Aminoácidos , Animales , Aplysia/genética , Aumento de la Célula , Células Cultivadas , Sistema Nervioso Central/fisiología , Clonación Molecular , Lymnaea , Datos de Secuencia Molecular , Neuronas Motoras/fisiología , Factores de Crecimiento Nervioso/genética , Proteínas del Tejido Nervioso , Neuritas/fisiología , Proteínas Tirosina Quinasas/metabolismo , Ratas , Receptores de Factores de Crecimiento , Receptores de Factor de Crecimiento Nervioso/metabolismo , Células Receptoras Sensoriales/fisiología , Especificidad de la Especie
8.
J Neurosci ; 33(17): 7565-73, 2013 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-23616561

RESUMEN

Although the importance of spaced training trials in the formation of long-term memory (LTM) is widely appreciated, surprisingly little is known about the molecular mechanisms that support interactions between individual trials. The intertrial dynamics of ERK/MAPK activation have recently been correlated with effective training patterns for LTM. However, whether and how MAPK is required to mediate intertrial interactions remains unknown. Using a novel two-trial training pattern which induces LTM in Aplysia, we show that the first of two training trials recruits delayed protein synthesis-dependent nuclear MAPK activity that establishes a unique molecular context involving the recruitment of CREB kinase and ApC/EBP and is an essential intertrial signaling mechanism for LTM induction. These findings provide the first demonstration of a requirement for MAPK in the intertrial interactions during memory formation and suggest that the kinetics of MAPK activation following individual experiences determines effective training intervals for LTM formation.


Asunto(s)
Aprendizaje/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Memoria a Largo Plazo/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Animales , Aplysia , Activación Enzimática/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Animales
9.
Learn Mem ; 20(10): 531-9, 2013 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-24042849

RESUMEN

Growth factor (GF) signaling is critically important for developmental plasticity. It also plays a crucial role in adult plasticity, such as that required for memory formation. Although different GFs interact with receptors containing distinct types of kinase domains, they typically signal through converging intracellular cascades (e.g., Ras-MEK-MAPK) to mediate overlapping functional endpoints. Several GFs have been implicated in memory formation, but due to a high level of convergent signaling, the unique contributions of individual GFs as well as the interactions between GF signaling cascades during the induction of memory is not well known. In this review, we highlight the unique roles of specific GFs in dendritic plasticity, and discuss the spatial and temporal profiles of different GFs during memory formation. Collectively, the data suggest that the roles of GF signaling in long-lasting behavioral and structural plasticity may be best viewed as interactive components in a complex molecular network.


Asunto(s)
Encéfalo/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Memoria/fisiología , Plasticidad Neuronal/fisiología , Transducción de Señal/fisiología , Animales , Humanos
10.
Behav Neurosci ; 138(1): 59-71, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38127524

RESUMEN

Drug exposure during adolescence, when the "reward" circuitry of the brain is developing, can permanently impact reward-related behavior into adulthood. Epidemiological studies show that opioid treatment during adolescence, such as pain management for a dental procedure or surgery, increases the incidence of psychiatric illness including substance use disorders. Moreover, the opioid epidemic currently in the United States is affecting younger individuals raising the impetus to understand the pathogenesis of the negative effects of opioids. One reward-related behavior that develops during adolescence is social behavior. We previously demonstrated that developmental changes in the nucleus accumbens reward region regulate social development in rats during sex-specific adolescent periods: early to mid-adolescence in males (postnatal day, P30-40) and preearly adolescence in females (P20-30). We thus hypothesized that the developmental stage of morphine exposure will differentially impact social behavior development such that drug administered during the female critical period would result in adult sociability deficits in females, but not males, and morphine administered during the male critical period would result in adult sociability deficits in males, but not females. We found that morphine exposure during the female critical period primarily resulted in deficits in sociability in females, while morphine exposure during the male critical period primarily resulted in deficits in sociability primarily in males. However, depending on the test performed and the social parameter measured, social alterations could be found in both sexes that received morphine exposure at either adolescent stage. These data indicate that when drug exposure occurs during adolescence, and how the endpoint data are measured, will play a large role in determining the effects of drug exposures on social development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Asunto(s)
Morfina , Cambio Social , Ratas , Femenino , Masculino , Animales , Morfina/farmacología , Analgésicos Opioides/farmacología , Conducta Social , Núcleo Accumbens
11.
Neurobiol Learn Mem ; 105: 117-24, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23727358

RESUMEN

Most long-term memories are formed as a consequence of multiple experiences. The temporal spacing of these experiences is of considerable importance: experiences distributed over time (spaced training) are more easily encoded and remembered than either closely spaced experiences, or a single prolonged experience (massed training). In this article, we first review findings from studies in animal model systems that examine the cellular and molecular properties of the neurons and circuits in the brain that underlie training pattern sensitivity during long-term memory (LTM) formation. We next focus on recent findings which have begun to elucidate the mechanisms that support inter-trial interactions during the induction of LTM. Finally, we consider the implications of these findings for developing therapeutic strategies to address questions of direct clinical relevance.


Asunto(s)
Aprendizaje/fisiología , Memoria a Largo Plazo/fisiología , Plasticidad Neuronal , Transducción de Señal , Animales , Humanos , Ratones , Investigación Biomédica Traslacional
12.
bioRxiv ; 2023 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-37205455

RESUMEN

Adolescence is a period of copious neural development, particularly in the 'reward' circuitry of the brain, and reward-related behavioral development, including social development. One neurodevelopmental mechanism that appears to be common across brain regions and developmental periods is the requirement for synaptic pruning to produce mature neural communication and circuits. We published that microglia-C3-mediated synaptic pruning also occurs in the nucleus accumbens (NAc) reward region during adolescence to mediate social development in male and female rats. However, both the adolescent stage in which microglial pruning occurred, and the synaptic pruning target, were sex specific. NAc pruning occurred between early and mid-adolescence in male rats to eliminate dopamine D1 receptors (D1rs), and between pre- and early adolescence in female rats (P20-30) to eliminate an unknown, non-D1r target. In this report, we sought to better understand the proteomic consequences of microglial pruning in the NAc, and what the female pruning target might be. To do this, we inhibited microglial pruning in the NAc during each sex's pruning period and collected tissue for mass spectrometry proteomic analysis and ELISA validation. We found that the proteomic consequences of inhibiting microglial pruning in the NAc were inversely proportional between the sexes, and a novel, female-specific pruning target may be Lynx1. Please note, if this preprint will be pushed further to publication it will not be by me (AMK), as I am leaving academia. So, I'm going to write more conversationally.

13.
bioRxiv ; 2023 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-37205324

RESUMEN

Evolutionarily conserved, peer-directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward-related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic 'reward' circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. In rats, we previously demonstrated that microglial synaptic pruning also mediates NAc and social development during sex-specific adolescent periods and via sex-specific synaptic pruning targets. In this report, we demonstrate that interrupting microglial pruning in NAc during adolescence persistently dysregulates social behavior towards a familiar, but not novel social partner in both sexes, via sex-specific behavioral expression. This leads us to infer that naturally occurring NAc pruning serves to reduce social behaviors primarily directed toward a familiar conspecific in both sexes, but in sex-specific ways.

14.
bioRxiv ; 2023 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-37205376

RESUMEN

Strong social support promotes a variety of positive health outcomes in humans and rodent models, while social isolation in rodents shortens lifespan, perceived social isolation (i.e. loneliness) can increase mortality by up to 50% in humans. How social relationships lead to these drastic health effects is unclear, but may involve modulation of the peripheral immune system. The reward circuitry of the brain and social behaviors undergo a critical period of development during adolescence. We published that microglia-mediated synaptic pruning occurs in the nucleus accumbens (NAc) reward region during adolescence to mediate social development in male and female rats. We hypothesized that if reward circuitry activity and social relationships directly impact the peripheral immune system, then natural developmental changes in the reward circuitry and social behaviors during adolescence should also directly impact the peripheral immune system. To test this, we inhibited microglial pruning in the NAc during adolescence, and then collected spleen tissue for mass spectrometry proteomic analysis and ELISA validation. We found that the global proteomic consequences of inhibiting microglial pruning in the NAc were similar between the sexes, but target-specific examination suggests that NAc pruning impacts Th1 cell-related immune markers in the spleen in males, but not females, and broad neurochemical systems in the spleen in females, but not males.

15.
bioRxiv ; 2023 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-37131669

RESUMEN

Drug exposure during adolescence, when the 'reward' circuitry of the brain is developing, can permanently impact reward-related behavior. Epidemiological studies show that opioid treatment during adolescence, such as pain management for a dental procedure or surgery, increases the incidence of psychiatric illness including substance use disorders. Moreover, the opioid epidemic currently in the United States is affecting younger individuals raising the impetus to understand the pathogenesis of the negative effects of opioids. One reward-related behavior that develops during adolescence is social behavior. We previously demonstrated that social development occurs in rats during sex-specific adolescent periods: early to mid-adolescence in males (postnatal day (P)30-40) and pre-early adolescence in females (P20-30). We thus hypothesized that morphine exposure during the female critical period would result in adult sociability deficits in females, but not males, and morphine administered during the male critical period would result in adult sociability deficits in males, but not females. We found that morphine exposure during the female critical period primarily resulted in deficits in sociability in females, while morphine exposure during the male critical period primarily resulted in deficits in sociability primarily in males. However, depending on the test performed and the social parameter measured, social alterations could be found in both sexes that received morphine exposure at either adolescent stage. These data indicate that when drug exposure occurs during adolescence, and how the endpoint data are measured, will play a large role in determining the effects of drug exposures on social development.

16.
bioRxiv ; 2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37162856

RESUMEN

Social networks and support are integral to health and wellness across the lifespan, and social engagement may be particularly important during aging. However, social behavior and social cognition decline naturally during aging across species. Social behaviors are in part supported by the 'reward' circuitry, a network of brain regions that develops during adolescence. We published that male and female rats undergo adolescent social development during sex-specific periods, pre-early adolescence in females and early-mid adolescence males. Although males and females have highly dimorphic development, expression, and valuation of social behaviors, there is relatively little data indicating whether social aging is the same or different between the sexes. Thus, we sought to test two hypotheses: (1) natural social aging will be sex-speciifc, and (2) social isolation stress restricted to sex-specific adolescent critical periods for social development would impact social aging in sex-specific ways. To do this, we bred male and female rats in-house, and divided them randomly to receive either social isolation for one week during each sex's respective critical period, or no manipulation. We followed their social aging trajectory with a battery of five tests at 3, 7, and 11 months of age. We observed clear social aging signatures in all tests administered, but sex differences in natural social aging were most robustly observed when a familiar social stimulus was included in the test. We also observed that adolescent isolation did impact social behavior, in both age-independent and age-dependent ways, that were entirely sex-specific. Please note, this preprint will not be pushed further to publication (by me, AMK), as I am leaving academia. So, it's going to be written more conversationally.

17.
J Neuroimmunol ; 384: 578204, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37774553

RESUMEN

Opioids have long been used for clinical pain management, but also have addictive properties that have contributed to the ongoing opioid epidemic. While opioid activation of opioid receptors is well known to contribute to reward and reinforcement, data now also suggest that opioid activation of immune signaling via toll-like receptor 4 (TLR4) may also play a role in addiction-like processes. TLR4 expression is enriched in immune cells, and in the nervous system is primarily expressed in microglia. Microglial phagocytosis is important for developmental, homeostatic, and pathological processes. To examine how morphine impacts microglial phagocytosis, we isolated microglia from adult male and female rat cortex and striatum and plated them in vitro at 10,000 (10K) or 50,000 cells/well densities. Microglia were incubated with neutral fluorescent microbeads to stimulate phagocytosis in the presence of one of four morphine concentrations. We found that the brain region from which microglia are isolated and plating density, but not morphine concentration, impacts cell survival in vitro. We found that 10-12 M morphine, but not higher concentrations, increases phagocytosis in striatal microglia in vitro independent of sex and plating density, while 10-12 M morphine increased phagocytosis in cortical microglia in vitro independent of sex, but contingent on a plating density. Finally, we demonstrate that the effect of 10-12 M morphine in striatal microglia plated at 10 K density is mediated via TLR4, and not µORs. Overall, our data suggest that in rats, a morphine-TLR4 signaling pathway increases phagocytic activity in microglia independent of sex. This may is useful information for better understanding the possible neural outcomes associated with morphine exposures.


Asunto(s)
Microglía , Morfina , Ratas , Masculino , Femenino , Animales , Morfina/farmacología , Microglía/metabolismo , Analgésicos Opioides/farmacología , Receptor Toll-Like 4/metabolismo , Encéfalo/metabolismo
18.
Biol Sex Differ ; 14(1): 31, 2023 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-37208759

RESUMEN

BACKGROUND: Damage to the cerebral vasculature can lead to vascular contributions to cognitive impairment and dementia (VCID). A reduction in blood flow to the brain leads to neuropathology, including neuroinflammation and white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is a risk factor for VCID which may be sex-dependent (female bias). METHODS: We compared the effects of mid-life metabolic disease between males and females in a chronic cerebral hypoperfusion mouse model of VCID. C57BL/6J mice were fed a control or high fat (HF) diet starting at ~ 8.5 months of age. Three months after diet initiation, sham or unilateral carotid artery occlusion surgery (VCID model) was performed. Three months later, mice underwent behavior testing and brains were collected to assess pathology. RESULTS: We have previously shown that in this VCID model, HF diet causes greater metabolic impairment and a wider array of cognitive deficits in females compared to males. Here, we report on sex differences in the underlying neuropathology, specifically white matter changes and neuroinflammation in several areas of the brain. White matter was negatively impacted by VCID in males and HF diet in females, with greater metabolic impairment correlating with less myelin markers in females only. High fat diet led to an increase in microglia activation in males but not in females. Further, HF diet led to a decrease in proinflammatory cytokines and pro-resolving mediator mRNA expression in females but not males. CONCLUSIONS: The current study adds to our understanding of sex differences in underlying neuropathology of VCID in the presence of a common risk factor (obesity/prediabetes). This information is crucial for the development of effective, sex-specific therapeutic interventions for VCID.


Reduced blood flow to the brain resulting from damaged blood vessels can lead to vascular dementia. Neuroinflammation and white matter damage are characteristics of vascular dementia. Middle-age is a time when obesity and prediabetes can increase risk for vascular dementia. This increase in risk is greater for women. A high fat diet causes obesity and prediabetes in mice. We compared the effects of diet-induced obesity in middle-age between males and females in a mouse model of vascular dementia. We have previously shown that a high fat diet causes greater obesity and prediabetes and a wider array of learning and memory problems in females compared to males. Here, we report on sex differences in the damage to the brain. White matter was negatively impacted by vascular dementia in males and high fat diet in females, with more severe prediabetes correlating with less white matter markers in females only. High fat diet led to an increase in activation of microglia (immune cells in the brain) in males but not in females. High fat diet also led to a decrease in pro-inflammatory and pro-resolving mediators expression in females but not males. The current study adds to our understanding of sex differences in underlying damage to the brain caused by vascular dementia in the presence of common risk factors (obesity and prediabetes). This information is needed for the development of effective, sex-specific treatments for vascular dementia.


Asunto(s)
Disfunción Cognitiva , Demencia Vascular , Estado Prediabético , Femenino , Ratones , Masculino , Animales , Dieta Alta en Grasa , Enfermedades Neuroinflamatorias , Caracteres Sexuales , Estado Prediabético/complicaciones , Ratones Endogámicos C57BL , Demencia Vascular/complicaciones , Demencia Vascular/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Obesidad
19.
Curr Opin Neurobiol ; 77: 102647, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36332416

RESUMEN

Sex differences in neural and behavioral development are integral to understanding neurodevelopmental, mental health, and neurodegenerative disorders. Much of the literature has focused on late prenatal and early postnatal life as a critical juncture for establishing sex-specific developmental trajectories, and data are now clear that immune signaling plays a central role in establishing sex differences early in life. Adolescence is another developmental period during which sex differences arise. However, we know far less about how immune signaling plays a role in establishing sex differences during adolescence. Herein, we review well-defined examples of sex differences during adolescence and then survey the literature to speculate how immune signaling might be playing a role in defining sex-specific adolescent outcomes. We discuss open questions in the literature and propose experimental design tenets that may assist in better understanding adolescent neurodevelopment.


Asunto(s)
Salud Mental , Maduración Sexual , Embarazo , Adolescente , Humanos , Femenino , Masculino , Caracteres Sexuales , Transducción de Señal
20.
Dev Cogn Neurosci ; 57: 101143, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35933922

RESUMEN

Adolescence is pivotal for neural and behavioral development across species. During this period, maturation occurs in several biological systems, the most well-recognized being activation of the hypothalamic-pituitary-gonadal axis marking pubertal onset. Increasing comparative studies of sex differences have enriched our understanding of systems integration during neurodevelopment. In recent years, immune signaling has emerged as a key node of interaction between a variety of biological signaling processes. Herein, we review the age- and sex-specific changes that occur in neural, hypothalamic-pituitary, and microbiome systems during adolescence. We then describe how immune signaling interacts with these systems, and review recent preclinical evidence indicating that immune signaling may play a central role in integrating changes in their typical and atypical development during adolescence. Finally, we discuss the translational relevance of these preclinical studies to human health and wellness.

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