Alicja L. Markowska

Age-related spatial reference and working memory deficits assessed in the water maze

Aged rats have spatial memory deficits relative to young rats. The extent of these deficits in intermediate-aged rats is not well established. The present study examined the pattern of age-related changes in spatial reference and working memory in four ages of Fischer-344 rats. Place discrimination (PD) in the Morris water maze measured spatial reference memory. Repeated acquisition (RA), a discrimination in which the escape platform location varied from session to session, measured spatial working memory. Fischer-344 rats, 4 months, 11 months, 17 months, and 24 months of age, were tested. Compared to 4-month-olds, 24-month-olds were significantly impaired on all six PD measures of performance, 17 months were significantly impaired on five PD measures, and 11 months were significantly impaired on only one PD measure. Only 24-month-olds had a significant working memory impairment in RA relative to 4 months. Reference and working memory measures were distinct as assessed by a principal components analysis. The results indicate a nonlinear age-related spatial memory decline in Fischer-344 rats from 4 to 24 months of age.

Individual differences in aging: Behavioral and neurobiological correlates

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Insulin-like growth factor-1 ameliorates age-related behavioral deficits.

Insulin-like growth factor-1 has been found to be involved in the regulation of several aspects of brain metabolism, neural transmission, neural growth and differentiation. Because decreased insulin-like growth factor-1 and/or its receptors are likely to contribute to age-related abnormalities in behavior, the strategy of replacing this protein is one potential therapeutic alternative. The present study was designed to assess whether cognitive deficits with ageing may be partially overcome by increasing the availability of insulin-like growth factor-1 in the brain. Fischer-344 x Brown Norway hybrid (F1) male rats of two ages (four-months-old and 32-months-old) were preoperatively trained in behavioral tasks and subsequently implanted with osmotic minipumps to infuse the insulin-like growth factor-1 (23.5 microg/pump) or a vehicle, i.c.v. Animals were retested at two weeks and four weeks after surgery. Insulin-like growth factor-1 improved working memory in the repeated acquisition task and in the object recognition task. An improvement was also observed in the place discrimination task, which assesses reference memory. Insulin-like growth factor-1 had no effect on sensorimotor skills nor exploration, but mildly reversed some age-related deficits in emotionality. These data indicate a potentially important role for insulin-like growth factor-1 in the reversal of age-related behavioral impairments in rodents.

Basal forebrain lesions and memory: Alterations in neurotensin, not acetylcholine, may cause amnesia.

Behavioral impairments produced by lesions of the nucleus basalis magnocellularis (NBM) are usually attributed to the loss of cholinergic cells. A comparison between the effects of 2 different neurotoxins, ibotenic (IBO) and quisqualic (QUIS) acid, reveals that this interpretation is inconsistent with the data. Rats were given injections of either IBO or QUIS into the NBM and tested on an alternation task in a T-maze. At the start of behavioral testing, both IBO and QUIS rats had impaired choice accuracy. At the end of behavioral testing, however, IBO rats, but not QUIS rats, were more impaired than controls, and IBO rats were more impaired than QUIS rats. IBO decreased choline acetyltransferase (ChAT) activity and [3H] neurotensin binding in the neocortex. QUIS decreased ChAT activity but did not change [3H] neurotensin binding. The cholinergic system may not be the critical component responsible for behavioral impairments following NBM lesions.

Acetyl-1-carnitine 2: Effects on learning and memory performance of aged rats in simple and complex mazes

Acetyl-1-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agents action on behavior are suggested.

Variable-interval probe test as a tool for repeated measurements of spatial memory in the water maze

Probe tests provide an important additional converging operation to identify the characteristics of cognitive processes being assessed by other behavioral measures. We introduce a new procedure using a variable-interval (VI) probe test to assess spatial memory in the water maze. Three groups of rats were trained in spatial discrimination with traditional platform trials. For the probe trials, 2 groups had no-platform (NP) probe trials in which the escape platform was unavailable for the entire trial. The 3rd group had variable interval (VI) probe trials, in which the escape platform was available only after a VI. The VI probe trial was a more sensitive measure of spatial memory than was the NP probe trial and was useful for repeated measurements of spatial memory, a characteristic not readily attainable with the NP probe trial.

Behavioral assessment of the senescence-accelerated mouse (SAM P8 and R1)

Senescence-accelerated mice (SAM P8 and R1) were behaviorally assessed in a cross-sectional study at 4 and 15 months of age. Behavioral measures included memory (place discrimination and repeated acquisition in a water maze), sensorimotor performance (turning in an alley, traversing bridges, wire rod hanging, and falls from a wire screen), psychomotor performance (open-field exploration), and emotionality (entries in a plus maze, grooming, and defecation in a plus maze and in an open field). In the water maze, aged P8 mice were impaired in place discrimination and in repeated acquisition tasks, demonstrating evidence of an age-related decline in spatial memory processing abilities. The demonstration of this impairment, however, was complicated by noncognitive factors, such as the tendency of many older P8 mice to float. Sensorimotor skill impairment was accelerated with age in P8 mice, but not in R1 mice, and this impairment was present despite the lack of age-related changes in body weight in P8 mice. Although P8 and R1 mice were not different in general activity at old age, P8 mice were substantially more hyperactive in an open field and in the plus maze than R1 mice when compared at young age. Independent of age, P8 mice demonstrated a reduction of anxiety-like behavior in the plus maze. Taken as a whole, the data suggest that although age-related behavioral alterations occur in the P8 mice, some of these changes are evident at 4 months of age. Thus, the behavioral abnormalities that exist not only represent an accelerated aging phenomenon but may also be considered a developmental pathology.

Nucleus basalis magnocellularis and memory: Differential effects of two neurotoxins

Although the cholinergic system is involved in memory, noncholinergic systems may also contribute to memory. Lesions of the nucleus basalis magnocellularis (NBM) produce behavioral impairments and reduction of cholinergic markers in the frontal cortex (FC). The present study compared the behavioral effects of lesions made with two different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid. IBO or QUIS was injected into the NBM, and rats were tested in three different tasks: cued delayed nonmatch-to-sample (CDNMS), spatial delayed nonmatch-to-sample (SDNMS), and spatial two-choice simultaneous discrimination (STCSD). IBO producted a greater behavioral impairment than QUIS in the CDNMS and the SDNMS, although QUIS produced a greater drop in choline acetyltransferase (ChAT) activity in the cortex than IBO. At the end of behavioral testing, IBO rats, but not QUIS rats, were impaired in the retention of both tasks. The fact that QUIS lesions produced a greater loss of NBM cholinergic neurons, as determined by decreased ChAT activity, but less of a behavioral impairment in both a spatial and nonspatial task, suggests that the loss of noncholinergic NBM neurons must contribute to the memory impairments following NBM cell loss.

Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats☆

Although the beneficial effects of diet restriction on longevity and the retardation of many somatic age-related processes are well established, the answer to the question of whether anti-aging effects of diet restriction extend to the brain and cognitive function remains unclear. In the present study, the effects of long-term dietary restriction (60% of ad-libitum calories) on an age-related alteration of memory and sensorimotor function have been investigated in Fischer 344 male rats at four different ages: 6 months, 12 months, 18 months, and 24 months. A major drop in reference memory of DR and AL rats occurred at the age of 18 months. The performance deficits in working memory tasks were observed in both diet groups at the age of 24 months. These results indicate that diet restriction failed to provide protection against age-related deficits in memory. Although DR rats outperformed AL rats in sensorimotor tasks throughout the life-span, the slope of the declining function in DR rats paralleled those of AL rats, suggesting that diet restriction failed to alter the rate of aging in sensorimotor performance, as well.

Acetyl-L-carnitine : behavioral, electrophysiological, and neurochemical effects

Aged rats were chronically administered acetyl-L-carnitine (AC) for 10 months. During this period they were tested on learning and sensorimotor tasks and were then subsequently tested electrophysiologically to assess induction and decay rates of long-term synaptic enhancement (LTE) in the hippocampus. Four groups were tested: young controls (4 mo-con), middle-aged controls (16 mo-con), old controls (24 mo-con), and old AC-treated rats (24 mo-AC). After completion of electrophysiological testing, each rat was sacrificed and investigated for age- or drug-related changes in three neurotransmitter markers; including, NMDA-sensitive glutamate receptors, high affinity choline uptake, and adenosine receptor number in the neocortex, hippocampus or caudate nucleus. Aging impaired spatial learning and there was a robust positive correlation between NMDA receptors in the hippocampus and acquisition of the spatial learning task. Induction of hippocampal LTE was reduced in 24 mo-AC rats and NMDA receptor number and high-affinity choline uptake in the frontal cortex was increased. Several suggestions are offered to explain the action of AC on these neurobiological parameters in old rats.