Syrian hamster neuroplasticity mechanisms fail as temperature declines to 15 °C, but histaminergic neuromodulation persists.

Previous research suggests that hippocampal neurons in mammalian hibernators shift their major function from memory formation at euthermic brain temperatures (T b = ~37 °C) to modulation of hibernation bout duration as T b decreases. This role of hippocampal neurons during torpor is based in part on in vivo studies showing that histamine (HA) infused into ground squirrel hippocampi lengthened torpor bouts by ~50%. However, it was unclear if HA acted directly on hippocampal neurons or on downstream brain regions via HA spillover into lateral ventricles. To clarify this, we used hippocampal slices to determine if HA would modulate pyramidal neurons at low levels of synaptic activity (as occurs in torpor). We tested the hypotheses that although LTP (a neuroplasticity mechanism) could not be generated at low temperatures, HA (via H2 receptors) would increase population spike amplitudes (PSAs) of Syrian hamster CA1 pyramidal neurons at low stimulation voltages and low temperatures. PSAs were recorded following Schaffer collateral stimulation from subthreshold levels to a maximum response plateau. We found that tetanus evoked LTP at 35 °C but not 15 °C; and at temperatures from 30 to 15 °C, HA significantly enhanced PSA at near threshold levels in slices from non-hibernating hamsters housed in "summer-like" or "winter-like" conditions and from hibernating hamsters. Cimetidine (H2 antagonist) blocked HA-mediated PSA increases in 8 of 8 slices; pyrilamine (H1 antagonist) had no effect in 7 of 8 slices. These results support our hypotheses and show that HA can directly enhance pyramidal neuron excitability via H2 receptors and thus may prolong torpor bouts.

Recovery of Syrian hamster hippocampal signaling following its depression during oxygen-glucose deprivation is enhanced by cold temperatures and by hibernation.

Signal transmission over a hippocampal network of CA3 and CA1 neurons in Syrian hamsters (Mesocricetus auratus), facultative hibernators, has not been fully characterized in response to oxygen-glucose deprivation (OGD). We hypothesized that during OGD, hippocampal signal transmission fails first at the synapse between CA3 and CA1 pyramidal neurons and that recovery of signal processing following OGD is more robust in hippocampal slices at cold temperature, from hamsters vs. rats, and from hibernating vs. non-hibernating hamsters. To test these hypotheses, we recorded fEPSPs and population spikes of CA1 neurons at 25°C, 30°C, and 35°C in 400µm slices over a 15min control period with the slice in oxygenated aCSF containing glucose (control solution), a 10min treatment period (OGD insult) where oxygen was replaced by nitrogen in aCSF lacking glucose, and a 30min recovery period with the slice in the control solution. The initial site of transmission failure during OGD occurred at the CA3-CA1 synapse, and recovery of signal transmission was at least, if not more (depending on temperature), complete in slices from hibernating vs. non-hibernating hamsters, and from non-hibernating hamsters vs. rats. Thus, hamster neuroprotective mechanisms supporting functional recovery were enhanced by cold temperatures and by hibernation.

Temporal relationships of blood pressure, heart rate, baroreflex function, and body temperature change over a hibernation bout in Syrian hamsters.

Hibernating mammals undergo torpor during which blood pressure (BP), heart rate (HR), metabolic rate, and core temperature (TC) dramatically decrease, conserving energy. While the cardiovascular system remains functional, temporal changes in BP, HR, and baroreceptor-HR reflex sensitivity (BRS) over complete hibernation bouts and their relation to TC are unknown. We implanted BP/temperature telemetry transmitters into Syrian hamsters to test three hypotheses: H-1) BP, HR, and BRS decrease concurrently during entry into hibernation and increase concurrently during arousal; H-2) these changes occur before changes in TC; and H-3) the pattern of changes is consistent over successive bouts. We found: 1) upon hibernation entry, BP and HR declined before TC and BRS, suggesting baroreflex control of HR continues to regulate BP as the BP set point decreases; 2) during the later phase of entry, BRS decreased rapidly whereas BP and TC fell gradually, suggesting the importance of TC in further BP declines; 3) during torpor, BP slowly increased (but remained relatively low) without changes in HR or BRS or increased TC, suggesting minimal baroreflex or temperature influence; 4) during arousal, increased TC and BRS significantly lagged increases in BP and HR, consistent with establishment of tissue perfusion before increased TC/metabolism; and 5) the temporal pattern of these changes was similar over successive bouts in all hamsters. These results negate H-1, support H-2 with respect to BP and HR, support H-3, and indicate that the baroreflex contributes to cardiovascular regulation over a hibernation bout, albeit operating in a fundamentally different manner during entry vs. arousal.

Neuroprotection supports signal processing in the hippocampus of Syrian hamsters, a facultative hibernator.

Studies on several species of mammalian seasonal hibernators (those hibernating only in winter) show that their neurons are more tolerant to hypoxia than those in non-hibernating species. Such tolerance has not been studied in facultative hibernators [e.g., Syrian hamsters (Mesocricetus auratus)], which can hibernate at any time of year. We tested the hypotheses that, when exposed to hypoxia, hamster hippocampal pyramidal cells more effectively support signal processing than do rat hippocampal neurons and this protection is enhanced in slices from hibernating versus non-hibernating hamsters and as temperature decreases. Population spike amplitudes (PSAs) were recorded from CA1 pyramidal cells. Slices were perfused in oxygenated artificial cerebral spinal fluid (O(2)ACSF) to establish a baseline. Oxygen was then replaced by nitrogen (N(2)ACSF) for 15 min, followed by a 30-min recovery period in O(2)ACSF. Three minutes after slices were returned to O(2)ACSF, PSAs recovered to 62.4 ± 6.8% of baseline in 15 slices from 8 non-hibernating hamsters but only to 22.7 ± 5.6% in 17 slices from 5 rats. Additionally, PSA recovery was greater in slices from hibernating than non-hibernating hamsters and recovery increased as temperature decreased. These significant differences (P ≤ 0.05) suggest Syrian hamsters are a useful model for studying naturally occurring neuroprotective mechanisms.

Decreasing temperature shifts hippocampal function from memory formation to modulation of hibernation bout duration in Syrian hamsters.

Previous studies in hibernating species have characterized two forms of neural plasticity in the hippocampus, long-term potentiation (LTP) and its reversal, depotentiation, but not de novo long-term depression (LTD), which is also associated with memory formation. Studies have also shown that histamine injected into the hippocampus prolonged hibernation bout duration. However, spillover into the ventricles may have affected brain stem regions, not the hippocampus. Here, we tested the hypothesis that decreased brain temperature shifts the major function of the hippocampus in the Syrian hamster (Mesocricetus auratus) from one of memory formation (via LTP, depotentiation, and de novo LTD) to increasing hibernation bout duration. We found reduced evoked responses in hippocampal CA1 pyramidal neurons following low-frequency stimulation in young (<30 days old) and adult (>60 days old) hamsters, indicating that de novo LTD was generated in hippocampal slices from both pups and adults at temperatures >20°C. However, at temperatures below 20°C, synchronization of neural assemblies (a requirement for LTD generation) was markedly degraded, implying that de novo LTD cannot be generated in hibernating hamsters. Nonetheless, even at temperatures below 16°C, pyramidal neurons could still generate action potentials that may traverse a neural pathway, suppressing the ascending arousal system (ARS). In addition, histamine increased the excitability of these pyramidal cells. Taken together, these findings are consistent with the hypothesis that hippocampal circuits remain operational at low brain temperatures in Syrian hamsters and suppress the ARS to prolong bout duration, even though memory formation is muted at these low temperatures.

Temperature modifies potentiation but not depotentiation in bidirectional hippocampal plasticity of Syrian hamsters (Mesocricetus auratus).

Previous studies have shown that one form of neuroplasticity, population spike (PS) potentiation, can be established in the hamster hippocampus at temperatures above 20 degrees C. Here, we tested three related hypotheses; namely, that in Syrian hamsters: (1) PS potentiation can be elicited below 20 degrees C and that at any constant temperature, potentiation can be described by a pair of sigmoidal functions matched to input/output curves; (2) potentiation can be partially reversed by depotentiation (a second and distinctive form of neuroplasticity); and (3) tetanus evokes long-term potentiation in slices from animals housed under conditions corresponding to various stages of the annual hibernation cycle. To test these hypotheses, we measured PS amplitudes and fEPSP slopes in CA1 pyramidal cells in hippocampal slices. We found that sigmoidal functions before and after tetanus showed PS enhancement at 18 degrees C and a larger enhancement at 28 degrees C, thereby supporting hypothesis 1. We also found that low-frequency stimulation reduced the amplitude of the potentiated PS by approximately 29% at both 18 degrees C and 28 degrees C, consistent with hypothesis 2; and that slices from nonhibernating hamsters on long and short photoperiods and from hamsters in hibernation all showed at least 40% increases in fEPSP slope following tetanus at a slice temperature of 23 degrees C, supporting hypothesis 3. Thus, bidirectional plasticity is present in hamsters. That is, both potentiation and depotentiation were readily evoked at 28 degrees C; potentiation was muted, while depotentiation (the reversal of the potentiation) remained robust at 18 degrees C. Moreover, potentiated responses could be elicited in slices from animals housed under diverse conditions.

LOXL null mice demonstrate selective dentate structural changes but maintain dentate granule cell and CA1 pyramidal cell potentiation in the hippocampus.

Lysyl oxidase-like protein (LOXL), part of the lysyl oxidase copper-dependent amine oxidase family, is expressed in the extracellular matrix and in the nucleus. It likely plays a role in cross-linking collagen and elastin, possibly modulating cellular functions. Immunohistochemical studies show the presence of LOXL in the pyramidal cell layer of the hippocampus; and in this study, we report that cells in the granule cell layer have significantly smaller somas in LOXL -/- compared to LOXL +/+ mice. In addition we tested the hypothesis that these structural alterations in the dentate granule layer were associated with synaptic efficacy and thus muted long-term potentiation in mice lacking the protein. Electrical recordings were obtained in 300-mum hippocampal slices in dentate and CA1 pyramidal cell layers in age-matched wild type and LOXL null mice. Potentiation in the CA1 cell layer of 10 LOXL -/- and 8 LOXL +/+ mice was 191.0+/-9.3% and 181.6+/-9.1%, respectively (mean+/-S.E.M.). Dentate potentiation was 120.8+/-7.0% and 121.0+/-3.4% in 11 LOXL -/- and 11 LOXL +/+ mice, respectively. No phenotypic difference in potentiation of population spike amplitude (or in EPSP slope) in either layer was observed. Thus, contrary to expectation, structural changes in the hippocampus of LOXL -/- mice did not affect synaptic remodeling in a manner that impaired the establishment of LTP.

Reduced feeding response to muscimol and neuropeptide Y in senescent F344 rats.

Many mammals experience spontaneous declines in their food intake and body weight near the end of life, a stage we refer to as senescence. We have previously demonstrated that senescent rats have blunted food intake responses to intracerebroventricular injections of neuropeptide Y (NPY). In the present study, we tested the hypothesis that responsiveness to GABA, a putative potentiator of NPY's effect, is also diminished. Young and old male F344 rats received injections of NPY, muscimol, (MUS, a GABA-A receptor agonist), combinations of these two agents, and vehicle [artificial cerebrospinal fluid (aCSF)] into the hypothalamic paraventricular nucleus (PVN). Both young and old presenescent rats increased their food intake in response to NPY, MUS, and the combination of the two (in comparison to injections of aCSF). The combination treatment was generally more effective than either NPY or MUS alone. These data are consistent with suggestions that both NPY and GABA play a role in the regulation of feeding behavior. Senescent rats exhibited an attenuated NPY-induced food intake, no increase in response to MUS, and a response to NPY + MUS that was no larger than that of NPY alone. We conclude that PVN injections of GABA, as well as NPY, are less effective in stimulating feeding in senescent rats and suggest that alterations in their signaling pathways play a role in the involuntary feeding decrease seen near the end of life.

Expression of NPY Y1 and Y5 receptors in the hypothalamic paraventricular nucleus of aged Fischer 344 rats.

Many mammals, nearing the end of life, spontaneously decrease their food intake and body weight, a stage we refer to as senescence. The spontaneous decrease in food intake and body weight is associated with attenuated responses to intracerebroventricular injections of neuropeptide Y (NPY) compared with old presenescent or with young adult rats. In the present study, we tested the hypothesis that this blunted responsiveness involves the number and expression of hypothalamic paraventricular nucleus (PVN) Y(1) and/or Y(5) NPY receptors, both of which are thought to mediate NPY-induced food intake. We found no significant difference in mRNA levels, via quantitative PCR, for Y(1) and Y(5) receptors in the PVN of senescent vs. presenescent rats. In contrast, immunohistochemistry indicated that the number of PVN neurons staining for Y(1) receptor protein was greater in presenescent compared with senescent rats. We conclude that a decreased expression and number of Y(1) or Y(5) receptors in the PVN cannot explain the attenuated responsiveness of the senescent rats to exogenous NPY.

Norepinephrine release in brown adipose tissue remains robust in cold-exposed senescent Fischer 344 rats.

Near the end of life, old F344 rats undergo a transition, marked by spontaneous and rapidly declining function. Food intake and body weight decrease, and these rats, which we call senescent, develop severe hypothermia in the cold due in part to blunted brown fat [brown adipose tissue (BAT)] thermogenesis. We tested the hypothesis that this attenuation may involve diminished sympathetic signaling by measuring cold-induced BAT norepinephrine release in freely moving rats using linear microdialysis probes surgically implanted into interscapular BAT 24 and 48 h previously. In response to 2 h at 15 degrees C, senescent rats increased BAT norepinephrine release 6- to 10-fold but did not maintain homeothermy. This increase was comparable to that of old presenescent (weight stable) rats that did maintain homeothermy during even greater cold exposure (2 h at 15 degrees C followed by 1.5 h at 8 degrees C). Tail temperatures, an index of vasoconstrictor responsiveness to cold, exhibited similar cooling curves in presenescent and senescent rats. Thus cold-induced sympathetic signaling to BAT and tail vasoconstrictor responsiveness remain robust in senescent rats and cannot explain their cold-induced hypothermia.