Hippocampal Memory Recovery After Acute Stress: A Behavioral, Morphological and Molecular Study

Abstract

Several studies have shown that a single exposure to stress may improve or impair learning and memory processes, depending on the timing in which the stress event occurs with relation to the acquisition phase. However, to date there is no information about the molecular changes that occur at the synapse during the stress-induced memory modification and after a recovery period. In particular, there are no studies that have evaluated—at the same time—the temporality of stress and stress recovery period in hippocampal short-term memory and the effects on dendritic spine morphology, along with variations in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. The aim of our study was to take a multidimensional approach to investigate concomitant behavioral, morphological and molecular changes induced by a single restraint stress exposure (2.5 h) and a recovery period of 6 and 24 h in rats. We found that acute stress elicited a reduced preference to explore an object placed in a novel position (a hippocampal-dependent task). These changes were accompanied by increased activity of LIM kinase I (LIMK; an actin-remodeling protein) and increased levels of NR2A subunits of NMDA receptors. After 6 h of recovery from stress, rats showed similar preference to explore an object placed in a novel or familiar position, but density of immature spines increased in secondary CA1 apical dendrites, along with a transient rise in GluA2 AMPA receptor subunits. After 24 h of recovery from stress, the animals showed a preference to explore an object placed in a novel position, which was accompanied by a normalization of NMDA and AMPA receptor subunits to control values. Our data suggest that acute stress produces reversible molecular and behavioral changes 24 h after stress, allowing a full reestablishment of hippocampal-related memory. Further studies need to be conducted to deepen our understanding of these changes and their reciprocal interactions.Adaptive stress responses are a promising avenue to develop interventions aiming at restoring hippocampal function impaired by repetitive stress exposure.

Deletion of hippocampal Glucocorticoid receptors unveils sex-biased microRNA expression and neuronal morphology alterations in mice

“…One fresh hemisphere was used for Golgi staining, using the FD Rapid GolgiStain™ kit (FD Neuro Technologies, Baltimore, MD, USA), as described ( Castaneda et al, 2015 ; Garcia-Rojo et al, 2017 ; Aguayo et al, 2018 ). Full details of dendritic complexity analyses are described within the supplementary methods.…”

Quantification of Dendritic Spines Remodeling under Physiological Stimuli and in Pathological Conditions

“…To highlight the role of dendritic spines in various context-dependent conditions, we have summarized dendritic spine remodeling in physiological processes and upon stimulation ( Table 1 ) induced by postsynaptic receptor antagonism [ 15 ], postsynaptic receptor agonism [ 16 , 17 ], genetic modifications [ 18 , 19 , 20 ], Chemically induced LTP [ 21 , 22 , 23 , 24 , 25 ], LTD (long-term depression) [ 26 ], sensory experience [ 27 , 28 ], spatial memory and learning [ 29 ], physical environmental stimuli [ 30 , 31 , 32 ]. Pathological processes ( Table 2 ) were categorized into brain diseases underling neurodegenerative (Alzheimer’s disease [ 33 , 34 , 35 ], Parkinson disease [ 36 ], Fragile X Syndrome [ 37 , 38 ], Down Syndrome [ 39 ], Rett Syndrome [ 40 , 41 ], Autism Spectrum Disorder [ 42 ], Huntingtin Disease [ 43 ]), neuropsychiatric (Schizophrenia [ 44 ], Depression [ 45 , 46 , 47 ]), Stroke [ 48 ], Epilepsy [ 49 ], and infectious diseases such as Prion Disease [ 50 ], HIV infection [ 51 ], Influenza Infection [ 52 ], Toxoplasmosis [ 53 ] and Antiviral Responses [ 54 ].…”

“…The high photostability of the dye acts as an effective tool to visualize cellular architecture including dendritic spines [ 96 ]. Spines in acute brain slices after chemical fixation [ 97 ] are labeled with DiI [ 18 , 21 , 32 , 35 , 47 , 53 , 96 ] or Golgi staining [ 15 , 34 , 46 , 49 , 52 ]. The key element in dendritic spine staining is to apply an appropriate, gentle tissue fixation to assess the relevant effects on spine structure and eliminate cascades of biochemical processes affecting biophysical properties of neuronal membrane caused by cell death [ 32 , 96 , 98 , 99 ], therefore the vital condition of cells is an important factor in accurate spine analysis [ 97 , 100 ].…”

“…Thus, the imaging speed is the main factor limiting the application of stochastic microscopy techniques in live imaging and in high throughput analysis. Thus, the studies related to physiological and pathological processes of spine remodeling are mainly addressed to fluorescent confocal microscopy [ 16 , 18 , 19 , 21 , 22 , 29 , 42 , 43 , 44 , 46 , 47 , 50 ] due to the possibility to analyze the higher number of spines than in EM [ 23 , 33 , 36 ], and STED [ 27 , 37 , 38 , 39 , 40 , 41 , 45 , 48 ]. The mechanisms underlying spine structure are mainly performed using EM and STED due to the high-resolution imaging.…”

“…Recently, methods for unsupervised classification or non-classification approaches have been developed, see [ 163 ] for a review. Thus, to assess the morphometric changes, either a classification scheme can be followed, where the percentages in spines categories are compared [ 19 , 29 , 33 , 42 , 43 , 44 , 46 ], or alternatively, a direct comparison of certain morphological parameters is performed [ 16 , 18 , 19 , 21 , 23 , 29 , 34 , 36 , 37 , 42 , 47 , 48 , 49 ]. Quite often, a dimensionless ratio of certain parameters is analyzed, the advantage of such an approach is that it measures only the changes in spine geometrical shape independently of changes in size [ 16 , 18 , 19 , 21 , 29 , 47 ].…”