Role of neuropeptide Y in adult neurogenesis of the hippocampus

Anxiety disorders are the largest group of brain disorders representing a major burden for the society. Recent evidence suggests a close relationship between anxiety disorders and neurons that are generated in the adult hippocampus. Proliferation, maturation and survival of hippocampal adult born neurons occur in the subgranular zone of the dentate gyrus and are mediated by a variety of environmental and cellular factors. Little is known, however, about the involvement of local circuitry mechanisms in adult neurogenesis. Recently, parvalbumin- positive neurons that are close to the subgranular zone have been suggested to play a crucial role in adult neurogenesis. Interestingly, these neurons are also expressing considerable amounts of Neuropeptide Y (NPY), an anxiolytic peptide with a proposed role in adult neurogenesis. In vitro experiments have shown that in particular the NPY Y1 receptor stimulates proliferation and survival of adult born neurons, whereas a role of the predominantly presynaptic Y2 receptor has not been determined yet. Y2 receptors are expressed on adult granule cells but also by local interneurons of the dentate hilus, where they inhibit release of NPY but also of the principal transmitters, glutamate or GABA. Thus, a possible function of Y2 receptors may only be apparent in vivo, when the complexity of the neurogenic niche with its local circuitry is preserved. Therefore we will elucidate the role of Y2 receptors in adult neurogenesis of the hippocampus in vivo and we will demonstrate the localization and function of Y2 receptors on an electron-microscopic, electrophysiological and behavioral level. 1) We will investigate the role of Y2 receptors in proliferation, maturation and survival of hippocampal adult born neurons. We will demonstrate that this effect is independent of Y1 receptor signaling. 2) We will investigate the role of NPY specifically released from parvalbumin-positive interneurons of the hippocampus on adult neurogenesis. We will further demonstrate the expression and functionality of Y2 receptors already in neuronal precursor cells and/or immature neurons of the hippocampus. 3) We will investigate a) the role of postsynaptic Y2 receptors on developing neurons of the subgranular zone and b) the role of presynaptic Y2 receptors on GABA-ergic interneuorns inhibiting GABA release. We will further demonstrate that these effects are independent of each other. 4) We will investigate the role of NPY in the modulation of fear memory by promoting adult neurogenesis, in addition to its action on the hippocampal circuitry. In summary, these experiments will clarify the specific interactions and behavioral relevance of a clearly identified interneuron class (NPY, parvalbumin and Y2 receptor positive, electrophysiologically and morphologically characterized) with newly developing neurons of the granule cell layer in vivo.

Anxiety disorders are the largest group of brain disorders representing a major burden for the society. Treatment for anxiety-disorders is limited to cognitive behavioral therapy and usually supported by pharmacotherapy. However, a significant portion of patients remains without treatment response. In particular, post-traumatic stress disorder patients are suffering from intense fear generalization and a chronic disease course. Thus, a better understanding of the underlying mechanisms may eventually open new avenues for therapeutic interventions. While several brain areas, such as the temporal lobe structures hippocampus and amygdala, are fundamental for controlling emotional affective memories, the pathological alterations and the involved neurotransmitter systems are only beginning to emerge. Recent evidence suggests a close relationship between anxiety disorders and neurons that are constantly born also in the hippocampus of the adult brain. Little is known, however, about the involvement of local circuitry mechanisms in adult neurogenesis. Neuropeptide Y (NPY), an anxiolytic peptide neurotransmitter with a proposed role in adult neurogenesis, is strongly expressed in the adult hippocampus. Importantly, in the mouse NPY Y2 receptors (Y2R) are present on mature granule cells of the hippocampal dentate gyrus, where they inhibit release of the excitatory neurotransmitter glutamate. In this project we investigated the role of Y2Rs in the suppression of fear memories and a possible relation to adult neurogenesis on neurochemical, anatomical, electrophysiological and most relevantly on behavioral levels. We demonstrated that Y2Rs in the hippocampus are strong suppressors of fear memories and promote their extinction. In fact they may act as a filter, which excludes irrelevant memories and shifts the focus towards important content for any given situation. In patients with post-traumatic stress disorder, fear generalization is a characteristic phenomenon, indicating that this kind of memory filter could be compromised. Y2Rs are thus well positioned to counteract fear generalization tendencies, although at the expense of reducing at the same time learning and memory for non-emotional content. Several neuronal subpopulations containing NPY are residing in the neurogenic niche of the adult hippocampus and each of them may address Y2R functioning in a unique manner. The fact that these neurons are not only local interneurons, but also projection neurons highlights the importance of NPY within a wider network of inhibitory control. Our data also suggest that Y2Rs do not directly activate or inhibit the proliferation or maturation of neuronal progenitor cells, but they rather seem to link general network activity to the maturation of new neurons. Since NPY is released upon strong and repetitive firing of neurons, such as during emotional challenges, increased network-activity may favor the maturation and inhibit the proliferation of new neurons also by activation of Y2Rs. These newly born neurons could suppress fear generalization by favoring discriminative learning and serve in the future as potential supportive therapy for post-traumatic stress disorder patients.