Learning and Memory Alterations Are Associated with Hippocampal N-acetylaspartate in a Rat Model of Depression as Measured by 1H-MRS

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume

Effects of CUMS and escitalopram treatment on normalized hippocampal volume.

<p>To account for variations in brain size, hippocampal volume is expressed relative to intracranial volume (ICV). The resulting ratios were multiplied by 1000. Data are presented as mean ± S.D. (n = 6 per group). Abbreviations: CON, control; CUMS, chronic unpredictable mild stress; ESC, escitalopram.</p

Schematic representation of animal group assignments and behavioural tests.

<p>Rats were randomly divided into 4 groups: control+saline, control+escitalopram, CUMS+saline and CUMS+escitalopram (n = 6 per group). Two weeks after the beginning of the CUMS regimen, rats received escitalopram (10 mg/kg, i.p.) or saline treatment once a day for another 4 weeks while the CUMS procedure was continued. Sucrose preference test and forced swimming test were measured before stress (0 week), before drug administration (2 week) and at the end of the experiment (6 week). Morris water maze and MRI scan were carried out at the end of the experiment.</p

Illustration of the voxel to the site of hippocampus for ¹H-MRS was presented, with associated magnetic resonance spectrographic imaging spectrum.

<p>(A) Left and right hippocampi are indicated by the white rectangles in coronal T₂-weighted imaging of rat brain. (B) Typical hippocampal ¹H-MRS with marked Myo-inositol (MI), choline-containing compounds (Cho), creatine and phosphocreatine (Cr), glutamate (Glu) and <i>N</i>-acetylaspartate (NAA) peaks.</p

Effects of CUMS and escitalopram treatment on sucrose preference (A), sucrose and water total intake (B) and immobility time in forced swimming test (C) Data are presented as mean ± S.D. (n = 6 per group).

<p>* <i>P</i><0.05, ** <i>P</i><0.01 vs. control+saline group, # <i>P</i><0.01 vs. CUMS+saline group.</p

Effects of CUMS and escitalopram treatment on acquisition and consolidation in the Morris water maze test.

<p>(A) In the acquisition trials, CUMS rats showed longer escape latency during training days 2–4, while escitalopram treatment restored the CUMS-induced longer latencies to control levels. In the probe trial, CUMS impaired memory retrieval as indicated by fewer crossing times of the platform position (B) and less time spent in the target quadrant (C), while escitalopram treatment restored the CUMS-induced impairment of memory retrieval to levels seen in controls. There was no significant difference of swim distance (D) and swim speed (E) among groups. Data are presented as mean ± S.D. (n = 6 per group). * <i>P</i><0.05, ** <i>P</i><0.01 vs. control+saline group. # <i>P</i><0.05, # # <i>P</i><0.01, vs. CUMS+saline group.</p

Effects of CUMS and escitalopram treatment on hippocampal ¹H-MRS measurements.

<p>Data are presented as mean ± S.D. (n = 6 per group).</p><p>**<i>P</i><0.005 vs. control+saline group,</p>#<p><i>P</i><0.05 vs. CUMS+saline group. Abbreviations: CON, control; CUMS, chronic unpredictable mild stress; ESC, escitalopram; NAA, N-acetylaspartate; Cr, creatine; Cho, choline-containing compounds; Glu, glutamate; MI, Myo-inositol.</p

Correlation analysis between NAA/Cr of the right hippocampus and the learning and memory test.

<p>(A–D) In the acquisition trials, a significant negative correlation was found between NAA/Cr of right hippocampus and the latency to find platform on day 1 (r = −0.478, <i>P</i> = 0.018), day 3 (r = −0.539, <i>P</i> = 0.007) and day 4 (r = −0.450, <i>P</i> = 0.027), although the correlation of day 2 (r = −0.348, <i>P</i> = 0.096) was not significant. (E) A significant positive correlation was shown between NAA/Cr of right hippocampus and the crossing number of platform (r = 0.654, <i>P</i> = 0.001). (F) There is a strong positive correlation between NAA/Cr of right hippocampus and the time spent in the target quadrant (r = 0.627, p = 0.001).</p