Learning and Aging Related Changes in Intrinsic Neuronal Excitability

A goal of many laboratories that study aging is to find a key cellular change(s) that can be manipulated and restored to a young-like state, and thus, reverse the age-related cognitive deficits. We have chosen to focus our efforts on the alteration of intrinsic excitability (as reflected by the postburst afterhyperpolarization, AHP) during the learning process in hippocampal pyramidal neurons. We have consistently found that the postburst AHP is significantly reduced in hippocampal pyramidal neurons from young adults that have successfully learned a hippocampus-dependent task. In the context of aging, the baseline intrinsic excitability of hippocampal neurons is decreased and therefore cognitive learning is impaired. In aging animals that are able to learn, neuron changes in excitability similar to those seen in young neurons during learning occur. Our challenge, then, is to understand how and why excitability changes occur in neurons from aging brains and cause age-associated learning impairments. After understanding the changes, we should be able to formulate strategies for reversing them, thus making old neurons function more as they did when they were young. Such a reversal should rescue the age-related cognitive deficits

Age-related enhancement of the slow outward calcium-activated potassium current in hippocampal CA1 pyramidal neurons in vitro

Aging is associated with learning deficits and a decrease in neuronal excitability, reflected by an enhanced post-burst afterhyperpolarization (AHP), in CA1 hippocampal pyramidal neurons. To identify the current(s) underlying the AHP altered in aging neurons, whole-cell voltage-clamp recording experiments were performed in hippocampal slices from young and aging rabbits. Similar to previous reports, aging neurons were found to rest at more hyperpolarized potentials and have larger AHPs than young neurons. Given that compounds that reduce the slow outward calcium-activated potassium current (sI(AHP)), a major constituent of the AHP, also facilitate learning in aging animals, the sI(AHP) was pharmacologically isolated and characterized. Aging neurons were found to have an enhanced sI(AHP), the amplitude of which was significantly correlated to the amplitude of the AHP (r = 0.63; p < 0.001). Thus, an enhanced sI(AHP) contributes to the enhanced AHP in aging. No differences were found in the membrane resistance, capacitance, or kinetic and voltage-dependent properties of the sI(AHP). Because enhanced AHP in aging neurons has been hypothesized to be secondary to an enhanced Ca2+ influx via the voltage-gated L-type Ca2+ channels, we further examined the sI(AHP) in the presence of an L-type Ca2+ channel blocker, nimodipine (10 μM). Nimodipine caused quantitatively greater reductions in the sIAHP in aging neurons than in young neurons; however, the residual sIAHP was still significantly larger in aging neurons than in young neurons. Our data, in conjunction with previous studies showing a correlation between the AHP and learning, suggest that the enhancement of the sIAHP in aging is a mechanism that contributes to age-related learning deficits

Associative learning elicits the formation of multiple-synapse boutons

The formation of new synapses has been suggested to underlie learning and memory. However, previous work from this laboratory has demonstrated that hippocampus-dependent associative learning does not induce a net gain in the total number of hippocampal synapses and, hence, a net synaptogenesis. The aim of the present work was to determine whether associative learning involves a specific synaptogenesis confined to the formation of multiple-synapse boutons (MSBs) that synapse with more than one dendritic spine. We used the behavioral paradigm of trace eyeblink conditioning, which is a hippocampus-dependent form of associative learning. Conditioned rabbits were given daily 80-trial sessions to a criterion of 80% conditioned responses in a session. During each trial, the conditioned stimulus (tone) and the unconditioned stimulus (corneal airpuff) were presented with an intervening trace interval of 500 msec. Brain tissue was taken for morphological analyses 24 hr after the last session. Unbiased stereological methods were used for obtaining estimates of the total number of MSBs in the stratum radiatum of hippocampal subfield CA1. The results showed that the total number of MSBs was significantly increased in conditioned rabbits as compared with pseudoconditioned or unstimulated controls. This conditioning-induced change, which occurs without a net synaptogenesis, reflects a specific synaptogenesis resulting in MSB formation. Models of the latter process are proposed. The models postulate that it requires spine motility and may involve the relocation of existing spines from nonactivated boutons or the outgrowth of newly formed spines for specific synaptogenesis with single-synapse boutons activated by the conditioning stimulation

BMP Signaling Mediates Effects of Exercise on Hippocampal Neurogenesis and Cognition in Mice

Exposure to exercise or to environmental enrichment increases the generation of new neurons in the adult hippocampus and promotes certain kinds of learning and memory. While the precise role of neurogenesis in cognition has been debated intensely, comparatively few studies have addressed the mechanisms linking environmental exposures to cellular and behavioral outcomes. Here we show that bone morphogenetic protein (BMP) signaling mediates the effects of exercise on neurogenesis and cognition in the adult hippocampus. Elective exercise reduces levels of hippocampal BMP signaling before and during its promotion of neurogenesis and learning. Transgenic mice with decreased BMP signaling or wild type mice infused with a BMP inhibitor both exhibit remarkable gains in hippocampal cognitive performance and neurogenesis, mirroring the effects of exercise. Conversely, transgenic mice with increased BMP signaling have diminished hippocampal neurogenesis and impaired cognition. Exercise exposure does not rescue these deficits, suggesting that reduced BMP signaling is required for environmental effects on neurogenesis and learning. Together, these observations show that BMP signaling is a fundamental mechanism linking environmental exposure with changes in cognitive function and cellular properties in the hippocampus

Water Vapor Near-UV Absorption: Laboratory Spectrum, Field Evidence, and Atmospheric Impacts

Absorption of solar radiation by water vapor in the near-UV region is a poorly-understood but important issue in atmospheric science. To better understand water vapor near-UV absorption, we constructed a cavity ring-down spectrometer with bandwidth of 5 cm-1 (~0.05 nm) and obtained water vapor absorption cross-sections at 1 nm increments in the 290-350 nm region. Water vapor displays structured absorption over this range with maximum and minimum cross-sections of 8.4×10-25 and 1.6×10-25 cm2/molecule. Major water vapor absorption bands were observed at 293-295, 307-313, 319, 321-322, and 325 nm, with cross-section values higher than 4.0×10-25 cm2/molecule. To obtain further insight into major water vapor absorption bands, we measured water vapor absorption cross-sections at 0.05 nm intervals in the 292-296, 306-314, and 317-326 nm region. Field UV residual spectra not only exhibited increased attenuation at higher atmospheric water vapor loadings but also showed structures suggested by the laboratory water vapor absorption spectrum. Spaceborne UV radiance spectra have spectral structures resembling the differential cross-section spectrum constructed from the laboratory wavelength-dependent water vapor absorption cross-sections presented here. Incorporating water vapor absorption cross-section data into a radiative transfer model yielded an estimated energy budget of 0.26 W/m2 for the standard U.S. atmosphere and 0.76 W/m2 for the tropics. This shows that water vapor near-UV absorption is an important contributor for climate simulation and ozone retrievals