Hippocampal plasticity: Development of connectivity and growth hormone modulation of place cells and behavior

The hippocampus is remarkably plastic and has the ability to modify its processes throughput the lifetime. During development, the hippocampus is exceedingly plastic as new neurons and connections are taking form. Nevertheless, the neural circuits of the hippocampus keep modifying in the adult. The factors contributing to hippocampal plasticity are still elusive. In this thesis, I present three papers in which I investigate different aspect of plasticity in the hippocampus using Long Evans rats. In the first paper using anatomical tracing approach, I showed that the first postnatal projections from the hippocampus and parahippocampus to the retrosplenial cortex are present at birth and display adult-like topography. These results indicate that the projections are independent on environmental factors. In the second and third papers, using adeno-associated viruses to overexpress the neuromodulator growth hormone (GH) or the antagonizing GH (aGH). In the second paper using behavioral tasks, I showed that GH enhanced hippocampal memory in a spontaneous recognition task, enhanced spine density. The aGH impaired memory performance in the Morris water maze task and decreased the spine density. In the third paper using single-unit recording, I found that GH tended to induce global remapping while aGH impaired remapping events. The results from the last to papers suggest that GH modulates hippocampal memory in which it reduces the interference of similar memories. Taken together, different factors contribute to changes in the hippocampus, and revealing such factors can have great importance for understanding the mechanisms behind memory deficiency as well as normal development and ageing

Development and topographical organization of projections from the hippocampus and parahippocampus to the retrosplenial cortex

The rat hippocampal formation (HF), parahippocampal region (PHR), and retrosplenial cortex (RSC) play critical roles in spatial processing. These regions are interconnected, and functionally dependent. The neuronal networks mediating this reciprocal dependency are largely unknown. Establishing the developmental timing of network formation will help to understand the emergence of this dependency. We questioned whether the long‐range outputs from HF‐PHR to RSC in Long Evans rats develop during the same time periods as previously reported for the intrinsic HF‐PHR connectivity and the projections from RSC to HF‐PHR. The results of a series of retrograde and anterograde tracing experiments in rats of different postnatal ages show that the postnatal projections from HF‐PHR to RSC display low densities around birth, but develop during the first postnatal week, reaching adult‐like densities around the time of eye‐opening. Developing projections display a topographical organization similar to adult projections. We conclude that the long‐range projections from HF‐PHR to RSC develop in parallel with the intrinsic circuitry of HF‐PHR and the projections of RSC to HF‐PHR

Hippocampal growth hormone modulates relational memory and the dendritic spine density in CA1

Growth hormone (GH) deficiency is associated with cognitive decline which occur both in normal aging and in endocrine disorders. Several brain areas express receptors for GH although their functional role is unclear. To determine how GH affects the capacity for learning and memory by specific actions in one of the key areas, the hippocampus, we injected recombinant adeno-associated viruses (rAAVs) in male rats to express green fluorescent protein (GFP) combined with either GH, antagonizing GH (aGH), or no hormone, in the dorsal CA1. We found that aGH disrupted memory in the Morris water maze task, and that aGH treated animals needed more training to relearn a novel goal location. In a one-trial spontaneous location recognition test, the GH treated rats had better memory performance for object locations than the two other groups. Histological examinations revealed that GH increased the dendritic spine density on apical dendrites of CA1, while aGH reduced the spine density. GH increased the relative amount of immature spines, while aGH decreased the same amount. Our results imply that GH is a neuromodulator with strong influence over hippocampal plasticity and relational memory by mechanisms involving modulation of dendritic spines. The findings are significant to the increasing aging population and GH deficiency patients