Role of Reuniens Nucleus Projections to the Medial Prefrontal Cortex and to the Hippocampal Pyramidal CA1 Area in Associative Learning

We studied the interactions between short- and long-term plastic changes taking place during the acquisition of a classical eyeblink conditioning and following high-frequency stimulation (HFS) of the reuniens nucleus in behaving mice. Synaptic changes in strength were studied at the reuniens-medial prefrontal cortex (mPFC) and the reuniens-CA1 synapses. Input/output curves and a paired-pulse study enabled determining the functional capabilities of the two synapses and the optimal intensities to be applied at the reuniens nucleus during classical eyeblink conditioning and for HFS applied to the reuniens nucleus. Animals were conditioned using a trace paradigm, with a tone as conditioned stimulus (CS) and an electric shock to the trigeminal nerve as unconditioned stimulus (US). A single pulse was presented to the reuniens nucleus to evoke field EPSPs (fEPSPs) in mPFC and CA1 areas during the CS-US interval. No significant changes in synaptic strength were observed at the reuniens-mPFC and reuniens-CA1 synapses during the acquisition of eyelid conditioned responses (CRs). Two successive HFS sessions carried out during the first two conditioning days decreased the percentage of CRs, without evoking any long-term potentiation (LTP) at the recording sites. HFS of the reuniens nucleus also prevented the proper acquisition of an object discrimination task. A subsequent study revealed that HFS of the reuniens nucleus evoked a significant decrease of paired-pulse facilitation. In conclusion, reuniens nucleus projections to prefrontal and hippocampal circuits seem to participate in the acquisition of associative learning through a mechanism that does not required the development of LTP

Effects of Enriched Physical and Social Environments on Motor Performance, Associative Learning, and Hippocampal Neurogenesis in Mice

We have studied the motor abilities and associative learning capabilities of adult mice placed in different enriched environments. Three-month-old animals were maintained for a month alone (AL), alone in a physically enriched environment (PHY), and, finally, in groups in the absence (SO) or presence (SOPHY) of an enriched environment. The animals' capabilities were subsequently checked in the rotarod test, and for classical and instrumental learning. The PHY and SOPHY groups presented better performances in the rotarod test and in the acquisition of the instrumental learning task. In contrast, no significant differences between groups were observed for classical eyeblink conditioning. The four groups presented similar increases in the strength of field EPSPs (fEPSPs) evoked at the hippocampal CA3-CA1 synapse across classical conditioning sessions, with no significant differences between groups. These trained animals were pulse-injected with bromodeoxyuridine (BrdU) to determine hippocampal neurogenesis. No significant differences were found in the number of NeuN/BrdU double-labeled neurons. We repeated the same BrdU study in one-month-old mice raised for an additional month in the above-mentioned four different environments. These animals were not submitted to rotarod or conditioned tests. Non-trained PHY and SOPHY groups presented more neurogenesis than the other two groups. Thus, neurogenesis seems to be related to physical enrichment at early ages, but not to learning acquisition in adult mice

Motor-Coordination-Dependent Learning, More than Others, Is Impaired in Transgenic Mice Expressing Pseudorabies Virus Immediate-Early Protein IE180

The cerebellum in transgenic mice expressing pseudorabies virus immediate-early protein IE180 (TgIE96) was substantially diminished in size, and its histoarchitecture was severely disorganized, resulting in severe ataxia. TgIE96 mice can therefore be used as an experimental model to study the involvement of cerebellar circuits in different learning tasks. The performance of three-month-old TgIE96 mice was studied in various behavioral tests, including associative learning (classical eyeblink conditioning), object recognition, spatial orientation (water maze), startle response and prepulse inhibition, and passive avoidance, and compared with that of wild-type mice. Wild-type and TgIE96 mice presented similar reflexively evoked eyeblinks, and acquired classical conditioned eyelid responses with similar learning curves for both trace and delay conditioning paradigms. The two groups of mice also had similar performances during the object recognition test. However, they showed significant differences for the other three tests included in this study. Although both groups of animals were capable of swimming, TgIE96 mice failed to learn the water maze task during the allowed time. The startle response to a severe tone was similar in both control and TgIE96 mice, but the latter were unable to produce a significant prepulse inhibition. TgIE96 mice also presented evident deficits for the proper accomplishment of a passive avoidance test. These results suggest that the cerebellum is not indispensable for the performance of classical eyeblink conditioning and for object recognition tasks, but seems to be necessary for the proper performance of water maze, prepulse inhibition, and passive avoidance tests

Hippocampal hypertrophy and sleep apnea: A role for the ischemic preconditioning?

The full impact of multisystem disease such as obstructive sleep apnoea (OSA) on regions of the central nervous system is debated, as the subsequent neurocognitive sequelae are unclear. Several preclinical studies suggest that its purported major culprits, intermittent hypoxia and sleep fragmentation, can differentially affect adult hippocampal neurogenesis. Although the prospective biphasic nature of chronic intermittent hypoxia in animal models of OSA has been acknowledged, so far the evidence for increased 'compensatory' neurogenesis in humans is uncertain. In a cross-sectional study of 32 patients with mixed severity OSA and 32 non-apnoeic matched controls inferential analysis showed bilateral enlargement of hippocampi in the OSA group. Conversely, a trend for smaller thalami in the OSA group was noted. Furthermore, aberrant connectivity between the hippocampus and the cerebellum in the OSA group was also suggested by the correlation analysis. The role for the ischemia/hypoxia preconditioning in the neuropathology of OSA is herein indicated, with possible further reaching clinical implications. © 2013 Rosenzweig et al