The parahippocampal region in the rodent brain includes the perirhinal, postrhinal, and entorhinal cortices, the presubiculum, and the parasubiculum. In recent years, the perirhinal and postrhinal cortices have been a focus in memory research because they supply highly processed, polymodal sensory information to the hippocampus, both directly and via the entorhinal cortex. Available evidence indicates that these cortices receive different complements of cortical information, which are then forwarded to the hippocampus via parallel pathways. Here we have summarized the cortical, subcortical, and hippocampal connections of the perirhinal and postrhinal cortices in order to provide further insight into the nature of the information that is processed by these regions prior to arriving in the hippocampus. As has been previously described, the cortical afferents of the rodent postrhinal cortex are dominated by structures known to be involved in the processing of visual and spatial information, whereas the cortical afferents of the perirhinal cortex result in remarkable convergence of polymodal sensory information. The two regions are also differentiated by their cortical efferents. The perirhinal cortex projects more strongly to piriform, frontal, and insular regions, whereas the postrhinal cortex projects preferentially to visual and visuospatial regions. The subcortical connections of the two regions provide further evidence that they have different functions. For example, the perirhinal cortex has strong reciprocal connections with the amygdala, which suggest involvement in processing affective stimuli. Subcortical input to the postrhinal cortex is dominated by projections from dorsal thalamic structures, particularly the lateral posterior nucleus. Although the perirhinal and postrhinal cortices are considered to contribute to the episodic memory system, many questions remain about their particular roles. A detailed description of the anatomical connections of the perirhinal and postrhinal cortices will permit the generation of new, anatomically guided, hypotheses about their role in episodic memory and other cognitive processes.

Objective: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). Methods: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. Results: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE—15.3 (4.5), raloxifene—16.0 (3.7), Rimostil—14.0 (2.7), and placebo—15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE—5.2(1.1), raloxifene—5.8(1.2), Rimostil—11.2(1.4), and placebo—7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. Conclusions: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

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A Val66Met single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies, along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically-determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val66Met SNP and [15O]H2O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working-memory related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val66Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.