Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response

Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.966 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, live and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.     

Purkinje cell loss by OX7-saporin impairs acquisition and extinction of eyeblink conditioning

The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of delay eyeblink conditioning in rats. Rats were given OX7-saporin or saline 2 wk before the start of eyeblink conditioning. The rats that reached a performance criterion of two consecutive days with 80% or greater conditioned responses were given 5 d of extinction training followed by 2 d of reacquisition training. Rats that received infusions of OX7-saporin had 77.2%-97.9% Purkinje cell loss and exhibited impaired acquisition and extinction. The amount of Purkinje cell loss was correlated with the magnitude of the acquisition and extinction impairments. The highest correlations between Purkinje cell number and the rate of acquisition were in lobule HVI and the anterior lobe. The highest negative correlation between Purkinje cell number and the percentage of conditioned responses during extinction was in the anterior lobe. The results indicate that cerebellar Purkinje cells, particularly in the anterior lobe and lobule HVI, play significant roles in acquisition and extinction of eyeblink conditioning.     

Facilitated acquisition of the classically conditioned eyeblink response in male rats after systemic IL-1β

Exposure to inescapable stressors enhances cue—dependent learning in male rats; enhanced learning is apparent as facilitated acquisition of the classically conditioned eyeblink respouse (CCER). The proinflammatory cytokines, in particular interleukin (IL)-1β, are presumed to orchestrate a number of acute-phase stress responses in rats, most notably fever, reduced feeding, and inactivity. Little is known of the impact proinflammatory cytokines have on learning and memory processes. Here, we address the effects of IL-1β treatment on acquisition of the classically conditioned eyeblink response 2 hours [?] after injection in male rats. Training was accomplished with a delay-type paradigm (500-ms conditional stimulus coterminating with a 10-ms periorbital unconditional stimulation). Facilitated acquisition was clearly apparent in rats treated with IL-1β (3.0 μg/kg). In a second experiment, we compared rats treated with 3.0 μg/kg to those treated with 1.0 μg/kg. Facilitated acquisition was reproduced, but the lower dose did not appreciably affect acquisition. These data further support contentions that IL-1β has anxiogenic properties, affecting basic new motor learning in a manner similar to that observed after exposure to stress.     

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA(A) receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre- and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations.     

Differential effects of progesterone and medroxyprogesterone on delay eyeblink conditioning in ovariectomized rats

Ovarian hormones modulate acquisition processes involved in classical conditioning. Although progesterone has been indirectly implicated, its role in classical conditioning of the eyeblink response has not been directly investigated. We assessed the effects of daily dosing of progesterone or medroxyprogesterone (MPA), a non-metabolized synthetic progestin, upon the acquisition of a classically conditioned eyeblink response in ovariectomized (OVX) female rats. Rats were dosed 4h prior to each training session with 0.1 or 1.5 mg/kg of either of these hormones or sesame oil. A delay conditioning paradigm was employed using a 500 ms conditioned stimulus coterminating with a 10 ms 10 V unconditioned stimulus. At the low dose, progesterone and MPA rats did differ from each other, with MPA-treated rats learning slower, but neither group differed from OVX-oil or Sham-oil controls. No group differences in acquisition were observed at the higher dose. During extinction trials, high-dose MPA-treatment and OVX-oil groups extinguished quicker than the high-dose progesterone-treated group. In addition, unconditional response (UR) amplitudes were lower in all OVX groups, regardless of hormone or oil treatment, compared to the sham-oil group. Since MPA did not affect extinction, it is likely the slower extinction in the progesterone-treated rats is due to a metabolite of progesterone. Corticosterone is discussed as a likely candidate for such a role. In addition, we found chronic absence of ovarian hormones decreased UR amplitudes, although differences in UR amplitudes were not associated with changes in the acquisition process. These results are discussed with respect to differences in the hormonal effects upon acquisition versus extinction processes and how these data may explain reports of learning differences in women based on oral contraceptive usage.     

Facilitated Acquisition of the Classically Conditioned Eyeblink Response in Male Rats After Systemic IL-1?

Exposure to inescapable stressors enhances cue-dependent learning in male rats; enhanced learning is apparent as facilitated acquisition of the classically conditioned eyeblink respouse (CCER). The proinflammatory cytokines, in particular interleukin (IL)-1beta, are presumed to orchestrate a number of acute-phase stress responses in rats, most notably fever, reduced feeding, and inactivity. Little is known of the impact proinflammatory cytokines have on learning and memory processes. Here, we address the effects of IL-1beta treatment on acquisition of the classically conditioned eyeblink response 2 hours [?] after injection in male rats. Training was accomplished with a delay-type paradigm (500-ms conditional stimulus coterminating with a 10-ms periorbital unconditional stimulation). Facilitated acquisition was clearly apparent in rats treated with IL-1beta (3.0 microg/kg). In a second experiment, we compared rats treated with 3.0 microg/kg to those treated with 1.0 microg/kg. Facilitated acquisition was reproduced, but the lower dose did not appreciably affect acquisition. These data further support contentions that IL-1beta has anxiogenic properties, affecting basic new motor learning in a manner similar to that observed after exposure to stress.     

Glucose injections into the dorsal hippocampus or dorsolateral striatum of rats prior to T-maze training: modulation of learning rates and strategy selection

The present experiments examined the effects of injecting glucose into the dorsal hippocampus or dorsolateral striatum on learning rates and on strategy selection in rats trained on a T-maze that can be solved by using either a hippocampus-sensitive place or striatum-sensitive response strategy. Percentage strategy selection on a probe trial (P(crit)) administered after rats achieved criterion (nine of 10 correct choices) varied by group. All groups predominately exhibited a response strategy on a probe trial administered after overtraining, i.e., after 90 trials. In experiment 1, rats that received intrahippocampal glucose injections showed enhanced acquisition of the T-maze and showed increased use of response solutions at P(crit) compared with that of unimplanted and artificial cerebral spinal fluid (aCSF)-treated groups. These findings suggest that glucose enhanced hippocampal functions to accelerate the rate of learning and the early adoption of a response strategy. In experiment 2, rats that received intrastriatal glucose injections exhibited place solutions early in training and reached criterion more slowly than did aCSF controls, with learning rates comparable to those of unoperated and operated-uninjected controls. Relative to unoperated, operated-uninjected and glucose-injected rats, rats that received intrastriatal aCSF injections showed enhanced acquisition of the T-maze and increased use of response solutions at P(crit). The unexpected enhanced acquisition seen after striatal aCSF injections suggests at least two possible interpretations: (1) aCSF impaired striatal function, thereby releasing competition with the hippocampus and ceding control over learning to the hippocampus during early training trials; and (2) aCSF enhanced striatal functioning to facilitate striatal-sensitive learning. With either interpretation, the results indicate that intrastriatal glucose injections compensated for the aCSF-induced effect. Finally, enhanced acquisition regardless of treatment was accompanied by rapid adoption of a response solution for the T-maze.     

Ontogenetic changes in the neural mechanisms of eyeblink conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that estavlish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

Changing the rate and hippocampal dependence of trace eyeblink conditioning: slow learning enhances survival of new neurons

Trace eyeblink conditioning in which a conditioned stimulus and unconditioned stimulus are separated by a gap, is hippocampal dependent and can rescue new neurons in the adult dentate gyrus from death (e.g., Beylin et al., 2001; Gould et al., 1999). Tasks requiring more training trials for reliable expression of the conditioned response are most effective in enhancing survival of neurons (Waddell & Shors, 2008). To dissociate hippocampal dependence from acquisition rate, we facilitated hippocampal-dependent trace eyeblink conditioning in two ways: a shorter trace interval and signaling the intertrial interval with a post-US cue. Trace conditioning with a shorter trace interval (250ms) requires an intact hippocampus, and acquisition is faster relative to rats trained with a 500ms trace interval (e.g., Weiss et al., 1999). Using excitotoxic hippocampal lesions, we confirmed that eyeblink conditioning with the 250 or 500ms trace interval is hippocampal dependent. However, training with the post-US cue was not hippocampal dependent. The majority of lesion rats in this condition reached criterion of conditioned responding. To determine whether hippocampal dependence is sufficient to rescue adult-generated neurons in the dentate gyrus, rats were injected with BrdU and trained in one of the three trace eyeblink arrangements one week later. Of these training procedures, only the 500ms trace interval enhanced survival of new cells; acquisition of this task proceeded slowly relative to the 250ms and post-US cue conditions. These data demonstrate that rate of acquisition and not hippocampal dependence determines the impact of learning on adult neurogenesis.     

Ontogenetic Changes in the Neural Mechanisms of Eyeblink Conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that establish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

Stress and Cytokine Effects on Learning: What Does Sex Have to Do With It?

Many studies have alluded to sexually dimorphic changes in behavior following stress. Although many have suggested that these changes are a function of stress-induced changes in learning and memory, there are questions regarding whether performance in those learning and memory tasks are influenced by stress-induced changes in drive more than in actual learning and memory processes. We used the classically conditioned eyeblink response (CCER) to determine whether slowed learning following stress in females can be explained by changes in unconditional response (UR) amplitude, a sign of a stress-induced shift in sensory reactivity. In addition, we had a second treatment group injected with the pro-inflammatory cytokine IL-1beta to serve as an interoceptive stress condition, a physiological stressor with minimal stimulation to the animal. Replicating the work by Shors and colleagues, we found that stressed female rats had slower acquisition of the conditioned response (CR), but we also found that an IL-1beta injection leads to a slowing of CR acquisition. However, in both cases, UR amplitude was lower in the treatment groups. We followed up these results by testing sensory reactivity through the acoustic startle response (ASR), where the magnitude of the ASR was marginally, but nonsignificantly, reduced by the same dose regimen of IL-1beta. Together, these experiments suggest that tailshock stress and immune signaling (IL-1beta) reduce sensory reactivity and the saliency of the stimuli used in the CCER, leading to slower learning in female rats.     

The Effect of Scopolamine in Older Rabbits Tested in the 750 ms Delay Eyeblink Classical Conditioning Procedure

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.     

The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer’s disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.     

Eyeblink classical conditioning and interpositus nucleus activity are disrupted in adult rats exposed to ethanol as neonates

Neonatal exposure to ethanol in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent cell loss in the cerebellum and deficits in coordinated motor performance. These rats are also impaired in eyeblink conditioning as weanlings and as adults. The current study examined single-unit neural activity in the interpositus nucleus of the cerebellum in adults following neonatal binge ethanol exposure. Group Ethanol received alcohol doses of 5.25 g/kg/day on postnatal days 4–9. Group Sham Intubated underwent acute intragastric intubation on postnatal days 4–9 but did not receive any infusions. Group Unintubated Control (from separate litters) did not receive any intubations. When rats were 3–7 mo old, pairs of extracellular microelectrodes were implanted in the region of the interpositus nucleus. Beginning 1 wk later, the rats were given either 100 paired or 190 unpaired trials per day for 10 d followed by 4 d of 100 conditioned stimulus (CS)-alone trials per day. As in our previous study, conditioned response acquisition in Group Ethanol rats was impaired. In addition, by session 5 of paired acquisition, Group Sham Intubated and Group Unintubated Control showed significant increases in interpositus nucleus activity, relative to baseline, in the CS–unconditioned stimulus interval. In contrast, Group Ethanol failed to show significant changes in interpositus nucleus activity until later in training. These results indicate that the disruption in eyeblink conditioning after early exposure to ethanol is reflected in alterations in interpositus nucleus activity.     

Stress and cytokine effects on learning: What does sex have to do with it?

Many studies have alluded to sexually dimorphic changes in behavior following stress. Although many have suggested that these changes are a function of stress-induced changes in learning and memory, there are questions regarding whether performance in those learning and memory tasks are influenced by stress-induced changes in drive more than in actual learning and memory processes. We used the classically conditioned eyeblink response (CCER) to determine whether slowed learning following stress in females can be explained by changes in unconditional response (UR) amplitude, a sign of a stress-induced shift in sensory reactivity. In addition, we had a second treatment group injected with the pro-inflammatory cytokine IL-1β to serve as an interoceptive stress condition, a physiological stressor with minimal stimulation to the animal. Replicating the work by Shors and colleagues, we found that stressed female rats had slower acquisition of the conditioned response (CR), but we also found that an IL-1β injection leads to a slowing of CR acquisition. However, in both cases, UR amplitude was lower in the treatment groups. We followed up these results by testing sensory reactivity through the acoustic startle response (ASR), where the magnitude of the ASR was marginally, but nonsignificantly, reduced by the same dose regimen of IL-1β. Together, these experiments suggest that tailshock stress and immune signaling (IL-1β) reduce sensory reactivity and the saliency of the stimuli used in the CCER, leading to slower learning in female rats.     

Eyeblink Classical Conditioning Differentiates Normal Aging from Alzheimer's Disease

Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.     

The effects of beta-noradrenergic receptor blockade on acquisition of eyeblink conditioning in 3-month-old F344 rats

There is evidence that blocking beta-noradrenergic receptors will cause deficits in some forms of learning. We investigated the effects of systemic injections of 1, 5, and 10 mg/kg doses of propranolol on acquisition of delay eyeblink conditioning in 3-month-old Fischer 344 rats. We presented a 3-kHz, 90-dB tone as a conditioning stimulus and a 6 psi airpuff as our unconditioned stimulus to freely moving rats. We monitored eyelid activity using EMG signals. The treatment subjects were injected with either propranolol or saline 0.5 h prior to daily training sessions. Two groups of control subjects, one receiving injections of saline and one receiving injections of 5 mg/kg propranolol, received daily training sessions with unpaired and randomized presentation of the tone and airpuff. Each daily training session for the treatment groups consisted of 27 paired training trials and 3 conditioned stimulus-alone training trials. Rats injected with saline vehicle or with 1 mg/kg propranolol achieved a 60% or better learned response rate within two training sessions. Rats injected with 5 or 10 mg/kg propranolol never achieved a response rate significantly different from animals that received unpaired, random presentations of the tone and airpuff stimuli. These results agree with prior studies from our lab that have shown a dose-dependent effect of beta-noradrenergic receptor blockade on learning in rabbit eyeblink conditioning as well as in a runway, motor learning paradigm. We believe that the beta-noradrenergic system plays an important role in learning and memory in more than one cerebellar-dependent learning paradigm.     

Age-related impairment in the 250-millisecond delay eyeblink classical conditioning procedure in C57BL/6 mice

In this study we tested 4-, 9-, 12-, and 18-month-old C57BL/6 mice in the 250-msec delay eyeblink classical conditioning procedure to study age-related changes in a form of associative learning. The short life expectancy of mice, complete knowledge about the mouse genome, and the availability of transgenic and knock-out mouse models of age-related impairments make the mouse an excellent species for expanding knowledge on the neurobiologically and behaviorally well-characterized eyeblink classical conditioning paradigm. Based on previous research with delay eyeblink conditioning in rabbits and humans, we predicted that mice would be impaired on this cerebellar-dependent associative learning task in middle-age, at ~9 months. To fully examine age differences in behavior in mice, we used a battery of additional behavioral measures with which to compare young and older mice. These behaviors included the acoustic startle response, prepulse inhibition, rotorod, and the Morris water maze. Mice began to show impairment in cerebellar-dependent tasks such as rotorod and eyeblink conditioning at 9 to 12 months of age. Performance in hippocampally dependent tasks was not impaired in any group, including 18-month-old mice. These results in mice support results in other species, indicating that cerebellar-dependent tasks show age-related deficits earlier in adulthood than do hippocampally dependent tasks.     

Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals

Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.     

Cortical barrel lesions impair whisker-CS trace eyeblink conditioning

Whisker deflection is an effective conditioned stimulus (CS) for trace eyeblink conditioning that has been shown to induce a learning-specific expansion of whisker-related cortical barrels, suggesting that memory storage for an aspect of the trace association resides in barrel cortex. To examine the role of the barrel cortex in acquisition and retrieval of trace eyeblink associations, the barrel cortex was lesioned either prior to (acquisition group) or following (retention group) trace conditioning. The acquisition lesion group was unable to acquire the trace conditioned response, suggesting that the whisker barrel cortex is vital for learning trace eyeblink conditioning with whisker deflection as the CS. The retention lesion group exhibited a significant reduction in expression of the previously acquired conditioned response, suggesting that an aspect of the trace association may reside in barrel cortex. These results demonstrate that the barrel cortex is important for both acquisition and retention of whisker trace eyeblink conditioning. Furthermore, these results, along with prior anatomical whisker barrel analyses suggest that the barrel cortex is a site for long-term storage of whisker trace eyeblink associations.