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The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.New neurons are produced in the brains of adult animals, including humans, throughout their lifespan (Altman 1963;Eriksson et al. 1998). Since one of the sites of adult brain neurogenesis is hippocampal formation, a brain structure involved in learning and memory, new neurons were expected to be involved in these phenomena. Following years of research, adult brain neurogenesis, along with synaptic strengthening, synaptic elimination/ weakening, and synaptogenesis are now regarded as four major types of plasticity required for formation and retention of memories (Bruel-Jungerman et al. 2007). However, the very evidence for the role of adult hippocampal neurogenesis in learning and memory remains limited, and in most cases, indirect (Leuner et al. We showed before (Kowalczyk et al. 2004) that cyclin D2, a protein involved in cell cycle regulation, is the only cyclin D (out of D1, D2, and D3) expressed in wild-type (WT) hippocampal neuronal progenitors expanded in vitro into neurospheres. Furthermore, careful analysis of the brains of cyclin D2 knockout mice (D2 KO mice) failed to reveal BrdU-positive neurons in the dentate gyrus of the hippocampal formation. We were also unsuccessful in increasing the number of newly generated cells in the hippocampus by a variety of stimulations, including introducing the mice to a novel environment, or even by a local brain injury. Notably, while adult brain neurogenesis of D2 KO mice is missing, their developmental neurogenesis allows for the formation of the brain, with all of the major structures present, though some of them are smaller. Also, neurogenesis outside of the central nervous system seems to be unaffected in these mice (Kowalczyk et al. 20...

No abstract

Active CREB (cAMP responsive element-binding protein) transcription factor is crucial for neuronal survival. Several members of the CREM/ICER (cAMP responsive element modulator/inducible cAMP early repressor) protein family may act as endogenous CREB antagonists. However, their involvement in a process of programmed cell death remains unexplored. Here we report that ICER may play such a role in neuronal apoptosis because it is upregulated in apoptotic neurons in vitro, and overexpression of ICER, delivered in adenoviral vector, evokes programmed cell death of three different kinds of cultured neurons, namely those derived from hippocampal dentate gyrus, cerebral cortex, and superior cervical ganglion. Reporter gene assay with a promoter containing a CREB-responsive sequence revealed a decrease in both basal and induced CRE-dependent gene expression in neurons overexpressing ICER. Finally, the level of expression of the anti-apoptotic protein Bcl-2, a well known CREB target, was markedly diminished in ICER-treated neurons. We suggest that the naturally occurring CREB functional antagonist ICER may have a specific function in programmed cell death of neurons, probably by silencing the expression of anti-apoptotic genes.