Brain areas interconnected to ventral pathway circuits are independently able to induce enhancement in object recognition memory and cause reversal in object recognition memory deficit.

AIMS: Ventral pathway circuits are constituted by the interconnected brain areas that are distributed throughout the brain. These brain circuits are primarily involved in processing of object related information in brain. However, their role in object recognition memory (ORM) enhancement remains unknown. Here, we have studied on the implication of these circuits in ORM enhancement and in reversal of ORM deficit in aging. METHODS: The brain areas interconnected to ventral pathway circuits in rat brain were activated by an expression of a protein called regulator of G-protein signaling 14 of 414 amino acids (RGS14414). RGS14414 is an ORM enhancer and therefore used here as a gain-in-function tool. ORM test and immunohistochemistry, lesions, neuronal arborization, and knockdown studies were performed to uncover the novel function of ventral pathway circuits. RESULTS: An activation of each of the brain areas interconnected to ventral pathway circuits individually induced enhancement in ORM; however, same treatment in brain areas not interconnected to ventral pathway circuits produced no effect. Further study in perirhinal cortex (PRh), area V2 of visual cortex and frontal cortex (FrC), which are brain areas that have been shown to be involved in ORM and are interconnected to ventral pathway circuits, revealed that ORM enhancement seen after the activation of any one of the three brain areas was unaffected by the lesions in other two brain areas either individually in each area or even concurrently in both areas. This ORM enhancement in all three brain areas was associated to increase in structural plasticity of pyramidal neurons where more than 2-fold higher dendritic spines were observed. Additionally, we found that an activation of either PRh, area V2, or FrC not only was adequate but also was sufficient for the reversal of ORM deficit in aging rats, and the blockade of RGS14414 activity led to loss in increase in dendritic spine density and failure in reversal of ORM deficit. CONCLUSIONS: These results suggest that brain areas interconnected to ventral pathway circuits facilitate ORM enhancement by an increase in synaptic connectivity between the local brain area circuits and the passing by ventral pathway circuits and an upregulation in activity of ventral pathway circuits. In addition, the finding of the reversal of ORM deficit through activation of an interconnected brain area might serve as a platform for developing not only therapy against memory deficits but also strategies for other brain diseases in which neuronal circuits are compromised.

RGS14414-Mediated Activation of the 14-3-3ζ in Rodent Perirhinal Cortex Induces Dendritic Arborization, an Increase in Spine Number, Long-Lasting Memory Enhancement, and the Prevention of Memory Deficits.

The remedy of memory deficits has been inadequate, as all potential candidates studied thus far have shown limited to no effects and a search for an effective strategy is ongoing. Here, we show that an expression of RGS14414 in rat perirhinal cortex (PRh) produced long-lasting object recognition memory (ORM) enhancement and that this effect was mediated through the upregulation of 14-3-3ζ, which caused a boost in BDNF protein levels and increase in pyramidal neuron dendritic arborization and dendritic spine number. A knockdown of the 14-3-3ζ gene in rat or the deletion of the BDNF gene in mice caused complete loss in ORM enhancement and increase in BDNF protein levels and neuronal plasticity, indicating that 14-3-3ζ-BDNF pathway-mediated structural plasticity is an essential step in RGS14414-induced memory enhancement. We further observed that RGS14414 treatment was able to prevent deficits in recognition, spatial, and temporal memory, which are types of memory that are particularly affected in patients with memory dysfunctions, in rodent models of aging and Alzheimer's disease. These results suggest that 14-3-3ζ-BDNF pathway might play an important role in the maintenance of the synaptic structures in PRh that support memory functions and that RGS14414-mediated activation of this pathway could serve as a remedy to treat memory deficits.

RGS14414 treatment induces memory enhancement and rescues episodic memory deficits.

Memory deficits affect a large proportion of the human population and are associated with aging and many neurologic, neurodegenerative, and psychiatric diseases. Treatment of this mental disorder has been disappointing because all potential candidates studied thus far have failed to produce consistent effects across various types of memory and have shown limited to no effects on memory deficits. Here, we show that the promotion of neuronal arborization through the expression of the regulator of G-protein signaling 14 of 414 amino acids (RGS14414) not only induced robust enhancement of multiple types of memory but was also sufficient for the recovery of recognition, spatial, and temporal memory, which are kinds of episodic memory that are primarily affected in patients or individuals with memory dysfunction. We observed that a surge in neuronal arborization was mediated by up-regulation of brain-derived neurotrophic factor (BDNF) signaling and that the deletion of BDNF abrogated both neuronal arborization activation and memory enhancement. The activation of BDNF-dependent neuronal arborization generated almost 2-fold increases in synapse numbers in dendrites of pyramidal neurons and in neurites of nonpyramidal neurons. This increase in synaptic connections might have evoked reorganization within neuronal circuits and eventually supported an increase in the activity of such circuits. Thus, in addition to showing the potential of RGS14414 for rescuing memory deficits, our results suggest that a boost in circuit activity could facilitate memory enhancement and the reversal of memory deficits.-Masmudi-Martín, M., Navarro-Lobato, I., López-Aranda, M. F., Delgado, G., Martín-Montañez, E., Quiros-Ortega, M. E., Carretero-Rey, M., Narváez, L., Garcia-Garrido, M. F., Posadas, S., López-Téllez, J. F., Blanco, E., Jiménez-Recuerda, I., Granados-Durán, P., Paez-Rueda, J., López, J. C., Khan, Z. U. RGS14414 treatment induces memory enhancement and rescues episodic memory deficits.