Injecting tetrodotoxin (TTX) into one hippocampus impaired avoidance of a place defined by distal cues while rats were on a slowly rotating arena. The impairment could be explained by a deficit in memory, navigation, or behavioral inhibition. Here, we show that the TTX injection abolished the ability of rats to organize place-avoidance behavior specifically when distal room and local arena cues were continuously dissociated. The results provide evidence that injecting TTX into one hippocampus specifically impaired the coordination of representations that support organized behavior because of the following: (1) rats normally coordinate separate room and arena avoidance memories; (2) the TTX injection spared spatial, relational, and representational memory, navigation, and behavioral inhibition; and (3) the TTX-induced impairment of place avoidance depended on the need to coordinate representations of local and distal stimuli.

Unilateral intrahippocampal injections of tetrodotoxin were used to temporarily inactivate one hippocampus during specific phases of training in an active allothetic place avoidance task. The rat was required to use landmarks in the room to avoid a room-defined sector of a slowly rotating circular arena. The continuous rotation dissociated room cues from arena cues and moved the arena surface through a part of the room in which foot-shock was delivered. The rat had to move away from the shock zone to prevent being transported there by the rotation. Unilateral hippocampal inactivations profoundly impaired acquisition and retrieval of the allothetic place avoidance. Posttraining unilateral hippocampal inactivation also impaired performance in subsequent sessions. This allothetic place avoidance task seems more sensitive to hippocampal disruption than the standard water maze task because the same unilateral hippocampal inactivation does not impair performance of the variable-start, fixed hidden goal task after procedural training. The results suggest that the hippocampus not only encodes allothetic relationships amongst landmarks, it also organizes perceived allothetic stimuli into systems of mutually stable coordinates. The latter function apparently requires greater hippocampal integrity.T he rodent hippocampus is a key neural system for processing information about the current spatial arrangement of stimuli and events (1-4), but it is still unclear what spatial computations the hippocampus actually does. One direction of the current experimental effort in this area is studying what aspects of spatial information the hippocampal network stores (5-12); a second is studying what spatial computations an intact hippocampal system is necessary for (13)(14)(15)(16)(17)(18)(19).It is crucial for this latter approach that there are behavioral paradigms, with clearly defined demands, that subjects must solve by using a limited set of potential solutions. The standard, variable-start, fixed hidden goal place navigation task in the water maze (20) has been invaluable because it allows the optimal solution to be readily distinguished from other less efficient strategies. The optimal strategy is for the rat to learn the allothetic relationships between distant, typically visual stimuli and the position of the escape platform. The absence of stable stimuli on the liquid substrate, like visual and tactile marks and odor cues, and the use of variable start locations make it difficult after standard training for the rat to solve the task optimally by using beacon-guided, praxis, or route-following strategies.Since the early eighties, place learning in the water maze has been used in lesion studies to elucidate the role of the hippocampus in spatial cognition (21,22). Selective bilateral lesions of the dentate gyrus and CA3-CA4 were found to severely impair water maze performance (23). However, in that study, unilateral dentate gyrus lesions, but not CA3-CA4 lesions disturbed water maze performance.One difficulty in interpreting t...

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Foraging rats learned to avoid footshock that was present in a part of a circular arena that was either stable or rotating slowly in a lighted room. The rotation dissociated spatial information in the separate reference frames of the room and arena. After learning to avoid the shocked region in either condition, in the absence of shock, memory for this place was expressed by simultaneous avoidance of an area defined in the reference frame of the room as well as of an area defined in the reference frame of the rotating arena. Spatial memories in these distinct reference frames were acquired, retrieved, and extinguished autonomously.