Hippocampus

The hippocampus, a brain region that is part of the limbic system in the medial temporal lobe, is critical to episodic memory, or the memory of autobiographical events. The hippocampus plays an important role in the consolidation of information from short-term memory into more permanent long-term memory and spatial memory which enables navigation. Hippocampal damage in humans has been linked to memory loss, such as in Alzheimer’s disease and other dementias, as well as in amnesia such as in the case of patient H.M. The role of the hippocampus has been well characterized in humans but is less understood in rodents due to contradictory findings. While rodents have served well as model organisms in developing our understanding of the cognitive map that is critical for spatial navigation, there has been substantial contention over the degree to which the rodent hippocampus supports non-spatial memory, specifically the memory for items or objects previously encountered. The overall objective of this research is to gain a better understanding of how neuronal circuits involving the hippocampus and perirhinal cortex function to support object memory in the brain. Chemogenetic technologies such as DREADDs (designer receptor exclusively activated by designer drugs) have proven to be effective tools in remote manipulation of neuronal activity. First, a series of behavioral tasks was used to validate the effects of DREADD inactivation in the CA1 region of dorsal hippocampus in C57BL/6J male mice. DREADD inhibition resulted in significant impairment in the spontaneous object recognition (SOR) task and of spatial memory in the Morris water maze. In conjunction, mice were implanted with bilateral perirhinal cortex guide cannulae to allow for temporary muscimol inactivation during distinct time points in the SOR task to further investigate the nature of its relationship with the hippocampus. The results reveal an unexpected role for the perirhinal cortex in the retrieval of strong object memory. Finally, Arc mRNA expression was quantified in CA1 of dorsal hippocampus and perirhinal cortex following both weak and strong object memory formation. The results indicate that the perirhinal cortex and hippocampus have distinct, yet complementary roles in object recognition memory and that distinction is gated by memory strength. Understanding the neural mechanisms supporting the weak-strong object memory distinction in mice is an important step not only in validating mice as a suitable model system to study episodic memory in humans, but also in developing treatments and understanding the underlying causes of diseases affecting long-term memory such as Alzheimer’s disease.

The causes of autism spectrum disorder (ASD) are not all known, but it is suspected that the serotonin transporter (SERT) plays an important role for some subjects with ASD. Mutations in the SLC6A4 gene, that encodes SERT, including the Ala56 mutation (Gly56Ala), have been found in some autism patients. This mutation makes the transporter more active and reduces the probability of serotonergic neurotransmission in the brain, which is linked to behavioral changes that are associated with core domain deficits of ASD 1.
Depression also has been linked to decreases in the availability of serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS), and is associated with reduced hippocampal neurogenesis. Selective serotonin reuptake inhibitors (SSRIs), drugs used to block SERTs, are used to treat depression and/or anxiety by inhibiting SERT to increase synaptic 5-HT levels.

The hippocampal-medial prefrontal circuit has been shown to serve a critical role
in decision making and goal directed actions. While the hippocampus (HF) exerts a direct
influence on the medial prefrontal cortex (mPFC), there are no direct return projections
from the mPFC to the HF. The nucleus reuniens (RE) of the midline thalamus is strongly
reciprocally connected with the HF and mPFC and represents the major link between
these structures.
We investigated the role of RE in functions associated with the hippocampus and
the mPFC -- or their interactions. Using two different inactivation techniques
(pharmacological and chemogenetic), we sought to further define the role of RE in spatial
working memory (SWM) and behavioral flexibility using a modified delayed non-match
to sample (DNMS) working memory task. We found that the reversible inactivation of
RE with muscimol critically impaired SWM performance, abolished well-established
spatial strategies and produced a profound inability to correct non-rewarded, incorrect choices on the T-maze (perseverative responding). We observed similar impairments in
SWM following the chemogenetic (DREADDs) inactivation of RE or selective RE
projections to the ventral HF. In addition, we showed that the inhibition of RE terminals
to the dorsal or ventral HF altered task related behaviors by increasing or decreasing the
time to initiate the task or reach the reward, respectively. Finally, we examined discharge
properties of RE cells across sleep-wake states in behaving rats. We found that the
majority of RE cells discharge at high rates of activity in waking and REM and at
significantly reduced rates in SWS, with a subpopulation firing rhythmically in bursts
during SWS. We identified five distinct subtypes of RE cells that discharged differently
across vigilant states; those firing at highest rates in waking (W1, W2), in REM sleep
(R1, R2) and SWS (S1). Given the differential patterns of activity of these cells, we
proposed they may serve distinct functions in waking – and possibly in SWS/REM sleep.
In sum, our findings indicate that RE is critically involved in mnemonic and
executive functions and the heterogeneous activity of these cells support a role for RE in
arousal/attention, spatial working memory and cognition.