Brainstem nucleus incertus controls contextual memory formation

Hippocampal pyramidal cells encode memory engrams, which guide adaptive behavior. Selection of engram-forming cells is regulated by somatostatin-positive dendrite-targeting interneurons, which inhibit pyramidal cells that are not required for memory formation. Here, we found that gamma-aminobutyric acid ( GABA)-releasing neurons of the mouse nucleus incertus (NI) selectively inhibit somatostatin-positive interneurons in the hippocampus, both monosynaptically and indirectly through the inhibition of their subcortical excitatory inputs. We demonstrated that NI GABAergic neurons receive monosynaptic inputs from brain areas processing important environmental information, and their hippocampal projections are strongly activated by salient environmental inputs in vivo. Optogenetic manipulations of NI GABAergic neurons can shift hippocampal network state and bidirectionally modify the strength of contextual fear memory formation. Our results indicate that brainstem NI GABAergic cells are essential for controlling contextual memories

Network Plasticity Involved in the Spread of Neural Activity Within the Rhinal Cortices as Revealed by Voltage-Sensitive Dye Imaging in Mouse Brain Slices

The rhinal cortices, such as the perirhinal cortex (PC) and the entorhinal cortex (EC), are located within the bidirectional pathway between the neocortex and the hippocampus. Physiological studies indicate that the perirhinal transmission of neocortical inputs to the EC occurs at an extremely low probability, though many anatomical studies indicated strong connections exist in the pathway. Our previous study in rat brain slices indicated that an increase in excitability in deep layers of the PC/EC border initiated the neural activity transfer from the PC to the EC. In the present study, we hypothesized that such changes in network dynamics are not incidental observations but rather due to the plastic features of the perirhinal network, which links with the EC. To confirm this idea, we analyzed the network properties of neural transmission throughout the rhinal cortices and the plastic behavior of the network by performing a single-photon wide-field optical recording technique with a voltage-sensitive dye (VSD) in mouse brain slices of the PC, the EC, and the hippocampus. The low concentration of 4-aminopyridine (4-AP; 40 μM) enhanced neural activity in the PC, which eventually propagated to the EC via the deep layers of the PC/EC border. Interestingly, washout of 4-AP was unable to reverse entorhinal activation to the previous state. This change in the network property persisted for more than 1 h. This observation was not limited to the application of 4-AP. Burst stimulation to neurons in the perirhinal deep layers also induced the same change of network property. These results indicate the long-lasting modification of physiological connection between the PC and the EC, suggesting the existence of plasticity in the perirhinal-entorhinal network

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities

Imprinting modulates processing of visual information in the visual wulst of chicks

BACKGROUND: Imprinting behavior is one form of learning and memory in precocial birds. With the aim of elucidating of the neural basis for visual imprinting, we focused on visual information processing. RESULTS: A lesion in the visual wulst, which is similar functionally to the mammalian visual cortex, caused anterograde amnesia in visual imprinting behavior. Since the color of an object was one of the important cues for imprinting, we investigated color information processing in the visual wulst. Intrinsic optical signals from the visual wulst were detected in the early posthatch period and the peak regions of responses to red, green, and blue were spatially organized from the caudal to the nasal regions in dark-reared chicks. This spatial representation of color recognition showed plastic changes, and the response pattern along the antero-posterior axis of the visual wulst altered according to the color the chick was imprinted to. CONCLUSION: These results indicate that the thalamofugal pathway is critical for learning the imprinting stimulus and that the visual wulst shows learning-related plasticity and may relay processed visual information to indicate the color of the imprint stimulus to the memory storage region, e.g., the intermediate medial mesopallium

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