Variation in early life maternal care predicts later long range frontal cortex synapse development in mice.

Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to understanding the effects of early life adversity

Induction of neuronal plasticity during adulthood. Role of cortical interneurons and plasticity-related molecules.

La complejidad del sistema nervioso de los vertebrados representa un reto a la hora de conocer su funcionamiento. Hace ya más de cien años que se postuló la neurona como unidad básica de procesamiento, generación y transmisión de la información a través de este sistema, y, con el paso de los años, ha evolucionado el conocimiento sobre esta unidad funcional. La idea clásica del sistema nervioso central (SNC) adulto es la de un tejido asombrosamente interconectado y complejo, pero prácticamente inmutable y muy poco adaptable a los cambios. No obstante, esta visión se ha ido desplazando, formándose una nueva idea del SNC adulto que, aunque de manera más limitada que durante el desarrollo, también tiene la propiedad de adaptarse a cambios tanto extrínsecos como intrínsecos, la denominada plasticidad neuronal. Esta plasticidad neuronal comprende múltiples procesos, desde los cambios en la eficiencia de las sinapsis (plasticidad sináptica) al remodelado de la estructura de las neuronas (plasticidad estructural) y la generación de nuevas células en el SNC adulto (neurogénesis). A su vez, estos fenómenos plásticos se encuentran mediados por neurotransmisores y otras moléculas que facilitan o limitan el remodelado de la estructura y conectividad de las neuronas. En la presente tesis voy a estudiar cómo afectan diversos tratamientos potenciadores de la plasticidad neuronal en el SNC a la estructura y conectividad de las neuronas en la corteza prefrontal medial, la corteza visual, el núcleo geniculado lateral, el colículo superior y la amígdala. Para ello he utilizado tres tratamientos cuya eficacia para para promover plasticidad neuronal ha sido previamente demostrada, pero cuyos efectos en la estructura de las interneuronas y la expresión de moléculas relacionadas con plasticidad neuronal no han sido explorados. Primero, he utilizado un paradigma de deprivación visual mediante el aislamiento de ratones adultos durante diez días para estudiar. A continuación, se han estudiado los efectos de una administración crónica de fluoxetina durante dos semanas en la amígdala basolateral de ratones adultos. Finalmente, se han analizado los efectos de la digestión enzimática de las redes perineuronales sobre la conectividad y la estructura de las interneuronas que expresan parvalbúmina en la corteza prefrontal medial de ratones adultos. En todos los casos se han descrito los efectos de estos tratamientos en la estructura de diferentes subpoblaciones de interneuronas sobre parámetros como la densidad de las espinas dendríticas o los botones axónicos, así como los efectos sobre la inervación perisomática que diferentes grupos de interneuronas efectúan sobre la zona perisomática de las neuronas piramidales en la corteza en el sistema nervioso central. En conjunto, los resultados obtenidos esbozan un escenario común en los tres tratamientos realizados: el incremento de la plasticidad neuronal se encuentra asociado con cambios estructurales de diferentes grupos de interneuronas, así como cambios en la expresión de moléculas relacionadas con la plasticidad en parámetros que previamente no habían sido descritos. Los resultados generales apuntan a un mecanismo general de descenso de la actividad de la circuitería cortical inhibitoria como mediador de la inducción de plasticidad neuronal en el sistema nervioso central adulto.The complexity of the nervous system of vertebrates represents a challenge to understand how it works. More than one hundred years ago, the neuron was postulated as the basic unit for processing, generating and transmitting information through this system, and, over the years, the knowledge about this functional unit has evolved. The classic idea of the adult central nervous system (CNS) is that of a surprisingly interconnected and complex tissue, but practically immutable and barely adaptable to change. However, this vision has been shifting, forming a new idea of the adult CNS which, although in a more limited way than during development, also has the property of adapting to both extrinsic and intrinsic changes, the so-called neuronal plasticity. This neuronal plasticity comprises multiple processes, from changes in the efficiency of synapses (synaptic plasticity) to the remodelling of the structure of neurons (structural plasticity) and the generation of new cells in the adult CNS (neurogenesis). In turn, these plastic phenomena are mediated by neurotransmitters and other molecules that facilitate or limit the remodeling of the structure and connectivity of neurons, the so-called plasticity-related molecules. In the present thesis, I studied how various neuronal plasticity-inducing treatments in the CNS affect the structure and connectivity of neurons in the medial prefrontal cortex, the visual cortex, the lateral geniculate nucleus, the superior colliculus and the amygdala. I have used three different treatments whose efficacy in promoting neuronal plasticity has been previously demonstrated, but whose effects on the structure of interneurons and the expression of molecules related to neuronal plasticity have not been completely explored. First, I have used a visual deprivation paradigm through dark exposure during ten days in adult mice. Next, the effects of chronic administration of fluoxetine for two weeks on the basolateral amygdala of adult mice. Finally, the effects of enzymatic digestion by ChondroitinaseABC of perineuronal networks on the connectivity and structure of parvalbumin-expressing interneurons in the medial prefrontal cortex of adult mice have been analyzed. In all cases the effects of these treatments on the structure of different subpopulations of interneurons on parameters such as the density of dendritic spines or axonic buttons have been described, as well as the effects on perisomatic innervation that different groups of interneurons carry out on the perisomatic area of pyramidal neurons in the cortex in the central nervous system. Together, the results obtained outlined a common scenario in the three treatments performed. This is, the increase of neuronal plasticity is associated with structural changes in different groups of interneurons, as well as changes in the expression of molecules related to plasticity in parameters that had not been previously described. The general results point to a general mechanism of decreased activity of inhibitory cortical circuitry as a mediator of the induction of neuronal plasticity in the adult central nervous system and open new perspectives into this field. Altogether, results exposed expand the current knowledge about the effects of plasticity-inducing treatments, as well as the role of plasticity-related molecules as mediators of this process and their possible use for the discovery of future treatments

GABAergic interneurons and prenatal ethanol exposure: from development to aging

Fetal Alcohol Spectrum Disorders are the most common non-genetic cause of neurodevelopmental disability worldwide. Individuals with Fetal Alcohol Spectrum Disorder experience clinical symptoms including differences in physical, cognitive and behavioral development beginning in early childhood, but continue to face challenges into adulthood. There is a critical need to examine the effects of prenatal ethanol exposure across early development, and to establish how the developmental effects of prenatal ethanol exposure may or may not progress in aging individuals. To contribute to these two areas, I asked how a binge-type prenatal ethanol exposure might affect: (1) early postnatal development of striatal neurons and, relate to the development of early motor behaviors over time, and (2) synaptic function in the medial prefrontal cortex, and affect the onset and severity of cognitive deficits in a transgenic mouse model of familial Alzheimer’s disease. I used whole-cell patch clamp electrophysiology to assess the functional and synaptic maturation of two populations of striatal neurons: striatal GABAergic interneurons and spiny striatal projection neurons, and the excitatory-inhibitory balance in deep layer medial prefrontal cortex pyramidal neurons. I found that prenatal ethanol exposure altered the postnatal developmental trajectory of striatal neurons in a sex-dependent manner, that coincided with sex-differences in the development of early motor behaviors, and morphological differences in striatal projection neurons. I also determined that prenatal ethanol exposure resulted in an earlier onset of deficits in GABAergic synaptic activity in cortical pyramidal neurons, that was an associated with a decreased number of parvalbumin expressing GABAergic interneurons, and an increase in intraneuronal APP/β-amyloid. These findings highlight the dynamic effects of prenatal ethanol exposure on synaptic function and behavioral outcomes during early development, and the lasting effects of prenatal ethanol exposure on neural circuits, modifying the aging process

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

The malleable brain: plasticity of neural circuits and behavior: A review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation (LTP) and long-term depression (LTD) respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by LTP and LTD, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.Fil: Schaefer, Natascha. University of Wuerzburg; AlemaniaFil: Rotermund, Carola. University of Tuebingen; AlemaniaFil: Blumrich, Eva Maria. Universitat Bremen; AlemaniaFil: Lourenco, Mychael V.. Universidade Federal do Rio de Janeiro; BrasilFil: Joshi, Pooja. Robert Debre Hospital; FranciaFil: Hegemann, Regina U.. University of Otago; Nueva ZelandaFil: Jamwal, Sumit. ISF College of Pharmacy; IndiaFil: Ali, Nilufar. Augusta University; Estados UnidosFil: García Romero, Ezra Michelet. Universidad Veracruzana; MéxicoFil: Sharma, Sorabh. Birla Institute of Technology and Science; IndiaFil: Ghosh, Shampa. Indian Council of Medical Research; IndiaFil: Sinha, Jitendra K.. Indian Council of Medical Research; IndiaFil: Loke, Hannah. Hudson Institute of Medical Research; AustraliaFil: Jain, Vishal. Defence Institute of Physiology and Allied Sciences; IndiaFil: Lepeta, Katarzyna. Polish Academy of Sciences; ArgentinaFil: Salamian, Ahmad. Polish Academy of Sciences; ArgentinaFil: Sharma, Mahima. Polish Academy of Sciences; ArgentinaFil: Golpich, Mojtaba. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Nawrotek, Katarzyna. University Of Lodz; ArgentinaFil: Paid, Ramesh K.. Indian Institute of Chemical Biology; IndiaFil: Shahidzadeh, Sheila M.. Syracuse University; Estados UnidosFil: Piermartiri, Tetsade. Universidade Federal de Santa Catarina; BrasilFil: Amini, Elham. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Pastor, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Wilson, Yvette. University of Melbourne; AustraliaFil: Adeniyi, Philip A.. Afe Babalola University; NigeriaFil: Datusalia, Ashok K.. National Brain Research Centre; IndiaFil: Vafadari, Benham. Polish Academy of Sciences; ArgentinaFil: Saini, Vedangana. University of Nebraska; Estados UnidosFil: Suárez Pozos, Edna. Instituto Politécnico Nacional; MéxicoFil: Kushwah, Neetu. Defence Institute of Physiology and Allied Sciences; IndiaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Turner, Anthony J.. University of Leeds; Reino Unid

Environmental enrichment and the striatum: the influence of environment on inhibitory circuitry within the striatum of environmentally enriched animals and behavioural consequences

The nervous system is integral to the healthy and whole functioning of an organism, mediating interactions with and responses to an organism’s surroundings. Environmental enrichment (EE) provides stimuli above that usually experienced within the laboratory environment, and has been shown to greatly impact the nervous system. The maturation of inhibitory circuitry controls the level of neuroplasticity and functional maturity present within neural systems. This thesis investigates the effect of EE upon the development of inhibitory circuitry within the striatum. The striatum is the entry nucleus to the basal ganglia, and as such mediates various cognitive and sensorimotor behaviours. This thesis investigates the effect of EE upon striatally-mediated behaviours of both juvenile and adult animals. This thesis demonstrates that exposure to an enriched environment accelerates maturation of inhibitory circuitry within the striatum and increases the number of active inhibitory interneurons within the adult striatum; improves problem solving and goal-orientated learning; and influences animal behaviours within automated testing apparatus. This work sheds light on the mechanisms by which EE impacts an important nucleus within the brain, and has implications for potential treatments of neurological disorders. Determining the optimum environment for healthy brain development may also aid in early education and intervention programs targeted at young children

Environmental enrichment and the striatum: the influence of environment on inhibitory circuitry within the striatum of environmentally enriched animals and behavioural consequences

The nervous system is integral to the healthy and whole functioning of an organism, mediating interactions with and responses to an organism’s surroundings. Environmental enrichment (EE) provides stimuli above that usually experienced within the laboratory environment, and has been shown to greatly impact the nervous system. The maturation of inhibitory circuitry controls the level of neuroplasticity and functional maturity present within neural systems. This thesis investigates the effect of EE upon the development of inhibitory circuitry within the striatum. The striatum is the entry nucleus to the basal ganglia, and as such mediates various cognitive and sensorimotor behaviours. This thesis investigates the effect of EE upon striatally-mediated behaviours of both juvenile and adult animals. This thesis demonstrates that exposure to an enriched environment accelerates maturation of inhibitory circuitry within the striatum and increases the number of active inhibitory interneurons within the adult striatum; improves problem solving and goal-orientated learning; and influences animal behaviours within automated testing apparatus. This work sheds light on the mechanisms by which EE impacts an important nucleus within the brain, and has implications for potential treatments of neurological disorders. Determining the optimum environment for healthy brain development may also aid in early education and intervention programs targeted at young children

The effects of prenatal malnutrition on the brain of adult rats: a study of anatomical, functional and molecular changes

Studies using a rat model of prenatal protein malnutrition (PPM) followed by nutritional rehabilitation show that PPM produces changes in the brain and behavior that endure throughout adulthood. Early studies investigated the vulnerability of the hippocampus, a structure involved in learning and memory, and reported permanent anatomical, physiological, and functional alterations. However, PPM also produces deficits in attentional processes, suggesting vulnerability across a broader cortical network including the parahippocampal region (PHR) and the prefrontal cortex (PFC). This thesis investigates the anatomical, functional, and molecular alterations in these regions resulting from PPM. This was accomplished through 4 studies: 1) A quantitative assessment of the number of neurons in the PHR and in the PFC using design-based stereology; 2) An evaluation of the impact of the PPM on metabolic activity in the PFC using the metabolic marker 2-[14C]deoxyglucose (2DG); 3) The identification of specific neuronal subtypes differentially activated during restraint stress in the PPM network using double-labelling immunohistochemistry; 4) The quantification of mRNA and protein expression of KCNJ3 (GIRK1), a potassium channel involved in regulating neural excitability, using quantitative polymerase chain reaction and Western blot analysis. Results showed that: 1) Neuron number in the PFC is unchanged by PPM, but two subfields of the PHR, the presubiculum and medial entorhinal cortex, exhibit significantly lower numbers in PPM rats; 2) Metabolic activity in specific PFC regions associated with attention including the prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices was reduced relative to controls while other regions, such as the hippocampus, were unaffected; 3) Exposure to stress evokes a significant increase in the number of inhibitory interneurons that are activated in the PFC of PPM rats which could likely contribute to the observed overall reduction in PFC activity; 4) For the KCNJ3 channel, PPM induces lower levels of mRNA and protein expression in the PFC while levels in the hippocampus and brain stem/basal ganglia are unchanged. Together, these data show that PPM creates permanent anatomical, functional, and molecular alterations selective to specific subfields, cell types, and molecules leading to an imbalance between excitatory and inhibitory processes in the PHR-PFC network of adult rats