Hj Krugers

Severe Early Life Stress Hampers Spatial Learning and Neurogenesis, but Improves Hippocampal Synaptic Plasticity and Emotional Learning under High-Stress Conditions in Adulthood

Early life stress increases the risk for developing stress-related pathologies later in life. Recent studies in rats suggest that mild early life stress, rather than being overall unfavorable, may program the hippocampus such that it is optimally adapted to a stressful context later in life. Here, we tested whether this principle of “adaptive programming” also holds under severely adverse early life conditions, i.e., 24 h of maternal deprivation (MD), a model for maternal neglect. In young adult male rats subjected to MD on postnatal day 3, we observed reduced levels of adult hippocampal neurogenesis as measured by cell proliferation, cell survival, and neuronal differentiation. Also, mature dentate granule cells showed a change in their dendritic morphology that was most noticeable in the proximal part of the dendritic tree. Lasting structural changes due to MD were paralleled by impaired water maze acquisition but did not affect long-term potentiation in the dentate gyrus. Importantly, in the presence of high levels of the stress hormone corticosterone, even long-term potentiation in the dentate gyrus of MD animals was facilitated. In addition to this, contextual learning in a high-stress environment was enhanced in MD rats. These morphological, electrophysiological, and behavioral observations show that even a severely adverse early life environment does not evolve into overall impaired hippocampal functionality later in life. Rather, adversity early in life can prepare the organism to perform optimally under conditions associated with high corticosteroid levels in adulthood.

Corticosterone and stress reduce synaptic potentiation in mouse hippocampal slices with mild stimulation

Elevation of circulating corticosterone levels, either through exogenous administration of the hormone or following stress exposure, is known to reduce hippocampal synaptic potentiation in rodents. It is presently debated whether this reduction is due to activation of hippocampal glucocorticoid receptors or is primarily caused in other brain structures projecting to the hippocampus. To address this issue, we examined whether synaptic potentiation in hippocampal slices from mice with low basal corticosterone levels was altered 1-4 h after a brief in vitro administration of 100 nM corticosterone. Population spike and field excitatory postsynaptic potential (fEPSP) were recorded in the cell and dendritic layers, respectively, of the CA1 area, in response to Schaffer collateral/commissural fiber stimulation. Basal characteristics of the stimulus-response relationship were not affected by corticosterone treatment, except that after corticosterone treatment the maximal fEPSP slope was reduced while the excitability ratio was increased. For studies on potentiation of the fEPSP and population spike, stimulus intensities were chosen to evoke half maximal responses before potentiation; this intensity was significantly lower for the fEPSP than for the population spike. Primed burst potentiation of the fEPSP but not population spike was significantly attenuated after corticosterone treatment. When using a more rigorous stimulation paradigm, i.e. theta burst potentiation, synaptic potentiation was not affected by corticosterone. Raising corticosterone levels in mice by exposure to a psychosocial stressor led to comparable results in subsequent in vitro experiments; stress reduced primed burst potentiation only of the fEPSP. These data support that corticosterone affects synaptic potentiation in the mouse via direct activation of hippocampal glucocorticoid receptors but only when using mild stimulation conditions.

A single social stress-experience alters glutamate receptor-binding in rat hippocampal CA3 area

The distribution of glutamate receptors in the rat hippocampus was investigated 24 h after the social stress of confrontation with a dominant opponent. AMPA-type glutamate receptors were labeled with the antagonist [3H]CNQX, and NMDA-type receptors were labeled with the competitive antagonist [3H]CGP39653. Increased [3H]CGP39653 labeling was exclusively found in the CA3 stratum radiatum and a decreased [3H]CNQX labeling was found in several hippocampal areas. Consequently, the ratio NMDA/AMPA binding was significantly increased in CA3 stratum oriens and CA3 stratum radiatum. These results suggest that a single unescapable social stress of defeat alters the impact of the excitatory neurotransmitter glutamate, which is restricted to hippocampal CA3 neurons. Possible consequences of the present findings are discussed.

Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E-deficient mice

IN mice with a homozygous or heterozygous deficiency for ApoE as well as in wild-type animals we established synaptic responsiveness in the hippocampal CA1 area following stimulation of the Schaffer/commissural fibers. The maximal population spike amplitude was significantly larger in wild-type animals than in mice lacking the ApoE gene, whereas the facilitation in population spike amplitude after paired pulse stimulation was most pronounced in homozygous mutant mice. Primed burst stimulation induced a lasting increase in population spike amplitude of all three groups. Apart from a more pronounced initial potentiation in the homozygous mutants, primed burst potentiation was comparable in all groups. Subsequent theta burst stimulation resulted in a long-term enhanced synaptic responsiveness which was impaired in heterozygous animals. The data show that both homo- and heterozygous ApoE mutant mice display altered synaptic plasticity in the hippocampal CA1 area.

Synthesis and organ distribution of [18F]fluoro-org 6141 in the rat: A potential glucocorticoid receptor ligand for positron emission tomography

For the synthesis of [18F]Fluoro-Org 6141 via a nucleophilic substitution reaction with 18F-, the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [18F]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized and 0.37 to 1.85 MBq of [18F]Fluoro-Org 6141 was administered intravenously. Kinetics of 18F activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of 18F activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that 18F activity uptake in the brain had not yet reached a maximum at this interval. Although [18F]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.

Altered expression of the cell cycle regulatory protein cyclin D1 in the rat dentate gyrus after adrenalectomy-induced granular cell loss.

The loss of dentate gyrus (DG) granular cells after removal of the rat adrenal glands (ADX) is mediated by a process that is apoptotic in nature. The present study was initiated to compare changes in the immunocytochemical distribution of the cell-cycle regulatory protein cyclin D1, which has been implicated in apoptosis, with the loss of DG granular cells after ADX. Our data indicate that cyclin D1-immunoreactivity (cyclin D1-ir) is enhanced in the rat dentate gyrus after adrenalectomy. The enhanced cyclin D1-ir shows a close relationship, both in time and space, with granular cell loss in the rat dentate gyrus that occurs after adrenalectomy. However, the enhanced cyclin D1-immunoreactivity was present in microglia and radial glia rather than in the dentate gyrus granular cells. This suggests that cyclin D1 is not directly involved in apoptosis of granular cells in the rat dentate gyrus after adrenalectomy.

THE RAT HIPPOCAMPUS AS A TARGET FOR PROLONGED STRESS - BIOCHEMICAL AND BEHAVIORAL-EFFECTS

The probability that an individual will suffer from a major depressive episode is often considered to be influenced by risk factors such as gender, premature parental loss, exposure to pathogenic parental rearing, personality, a history of traumatic events, a previous history of major depression, low social support, recent stressful life events and difficulties and predisposing genetic influences. Although several studies suffer from methodological limitations, major depression (endogenous depression) is regarded as a multifactorial disorder and understanding its etiology requires the rigorous integration of several risk factors.