Water maze training in aged rats: effects on brain metabolic capacity and behavior.

The effects of Morris water maze training on brain metabolism and behavior were compared between aged (20-22 months) and young (2-4 months) Fischer 344 male rats. Each group had yoked controls, which swam the same amount of time as the trained rats but without the platform. This was followed after 9 days by quantitative histochemical mapping of brain cytochrome oxidase, the terminal enzyme for cellular respiration. The aged rats spent a significantly lower percent of time in the correct quadrant and had a longer latency to escape to the hidden platform, relative to the young rats. Metabolic differences between trained aged and young rats were found in regions related to escape under stress: perirhinal cortex, basolateral amygdala and lateral habenula; and vestibular nuclei that guide orientation in three-dimensional space. These differences were not found in the yoked swimming rats. The results suggest that, at the time point investigated, water maze training in aged Fischer 344 rats produces altered oxidative energy metabolism in task-relevant limbic and vestibular regions.

Protein synthesis inhibition blocks the induction of mossy fiber long-term potentiation in vivo.

Protein synthesis inhibitors block the maintenance of NMDA receptor-dependent long-term potentiation (LTP) both in vivo and in vitro. Protein synthesis inhibitors block mossy fiber(MF) LTP maintenance in vitro, but little is known about the effect of protein synthesis inhibitors on either induction or maintenance in MF-LTP in vivo. Here we study the role of protein synthesis in the induction of long-term potentiation at the mossy fiber-CA3 hippocampal synapse in vivo in anesthetized rats. The protein synthesis inhibitor anisomycin was administered at different doses (0.04, 10, or 40 nmol) into area CA3 15 min before delivering high-frequency stimulation (two times at 100 Hz, 1 sec). Anisomycin blocked MF-LTP induction in a dose-dependent manner; both 40 and 10 nmol blocked MF-LTP induction, but a lower dose of 0.04 nmol was without effect. The inhibitory effect of anisomycin on protein synthesis was determined by measuring the incorporation of [(35)S]methionine into the newly synthesized proteins. Percentages of protein synthesis inhibition were determined by comparing [(35)S] incorporation of anisomycin-treated samples with vehicle controls. Doses of 0.04, 10, or 40 nmol of anisomycin produced 21, 82, or 83% inhibition of [(35)S]methionine incorporation, respectively. The effect of anisomycin was verified using a single dose of the protein synthesis inhibitor cycloheximide (40 nmol). Cycloheximide also blocked MF-LTP induction. These results suggest that protein synthesis plays an important role in the induction of mossy fiber long-term potentiation in vivo.

Opioid receptor modulation of mossy fiber synaptogenesis: independence from long-term potentiation.

Long-term potentiation (LTP) at the mossy fiber-CA3 synapse of the rat hippocampus is an NMDA receptor-independent form of synaptic plasticity that is sensitive to opioid receptor antagonists [12]. In the present study, Timm's stain, a zinc detecting histological marker commonly used to infer synaptogenesis in the mossy fiber projection, was used to examine whether synaptogenesis occurs in response to mossy fiber LTP induction in the adult rat in vivo. Seven days following the induction of mossy fiber LTP by non-seizure-inducing high-frequency stimulation of the mossy fibers, a prominent band of Timm's staining appeared bilaterally in the infrapyramidal region of the stratum oriens in area CA3. Staining was more prominent on the side contralateral to the stimulation. Systemic administration of the opioid receptor antagonist naloxone, sufficient to block mossy fiber LTP induction, did not block the development of Timm's staining in the infrapyramidal region ipsilateral to stimulation, but it did block stimulation-induced increases in Timm's staining observed contralaterally. Systemic administration of (+/-) CPP, a competitive NMDA receptor-antagonist, by contrast, did not block the induction of LTP and did not alter the increase in Timm's staining observed either ipsilaterally or contralaterally. The increase in Timm's staining in the infrapyramidal region suggests that mossy fiber synaptogenesis occurs in response to non-seizure inducing stimulation. Synaptogenesis does not appear to be directly related to opioid receptor-dependent mossy fiber LTP induction, because it occurs in the presence of naloxone which blocks LTP. The mossy fiber synaptogenesis occurring contralaterally appears to be regulated by endogenous opioid peptides, because it is blocked by naloxone.