Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat

Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 μg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 μg/side), a GABA_A receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 μg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.     

Behavioural arousal and its habituation in the squirrel fish, Holocentrus rufus: the role of the telecephalon

Squirrel fish were captured, maintained for 2 days and then tested for their responses to stimuli in laboratory aquaria. A tap on the side of the aquarium or a shadow moving overhead elicited an arousal response involving a reduction in opercular movements, movement of the pectoral fins, and erection of the spiny dorsal fin. This latter response, when regularly provoked by a moving shadow at 15-s intervals, decreased in duration and habituated. When fish were restricted in a wire mesh trough and the stimulus was the onset of illumination to one eye at 15-s intervals, responses were quantitatively similar although shorter in duration. A series of stimuli delivered to one eye until habituation followed by a series to the other eye reduced the duration of initial responses and the number of trials for habituation of responses to stimuli delivered to the second eye. Responses were equivalent regardless of which eye (left or right) was first presented with stimuli. Section of the telencephalic anterior commissure considerably restricted the transfer of information about experience of stimuli presented to the first eye. Commissural section, combined with unilateral lesions in the posterior-medial telencephalon, severely impaired habituation of responses to the contralateral eye. Lateral lesions had no effect. The results are discussed in relation to the visual projection in Holocentrus and telecephalic involvement in arousal and its habituation in teleosts as a whole.     

Exploratory behavior as a function of environmental novelty and complexity in male and female rats

Laboratory rats show a positive response to low- and nonstressful novel events. The novel event may involve a number of aspects of the stimulus field. It is usually associated with a change in amount of environmental complexity. Most studies concerning novelty-related behavior involve the introduction of novel objects or the rearrangement of familiar objects. The present purpose was to measure exploratory behavior in response to environments of increased and decreased complexity. Both directions of environmental change are conditions of novelty. A two-way manipulation of increasing and decreasing the complexity of the environment was used. Rats of both sexes showed increased exploration to exposure to novelty, no matter which manipulation was applied; however, female and male rats behaved differently to the two types of novelty. Males responded more to novelty from the introduction of an unfamiliar object. The results indicate novel stimulation, whether of increasing or decreasing complexity, has reward properties. Perhaps the male-specific behavior directed toward unfamiliar objects may serve an adaptive function.     

Delay-dependent involvement of the rat entorhinal cortex in habituation to a novel environment

Evidence has accumulated that the entorhinal cortex (EC) is involved in memory operations underlying formation of a long-term memory. Because entorhinal-lesioned rats are impaired for long delays in delayed matching and non-matching to sample tasks, it has been proposed that EC contributes to the maintenance of information in short-term memory. In the present study, we asked whether such a time-limited role applies also when learning complex spatial information in a novel environment. We therefore examined the effects of EC lesions on habituation in an object exploration task in which a delay of either 4 min or 10 min is imposed between successive sessions. EC-lesioned rats exhibited a deficit in habituation at 10 min but not 4 min delays. Following habituation, reactions to spatial change (object configuration) and non-spatial change (novel object) were also examined. EC-lesioned rats were impaired in detecting the spatial change but were able to detect a non-spatial change, irrespective of the delay. Overall, the results suggest that EC is involved in maintaining a large amount of novel, multidimensional information in short-term memory therefore enabling formation of long-term memory. Switching to a novelty detection mode would then allow the animal to rapidly adapt to environmental changes. In this mode, EC would preferentially process spatial information rather than non-spatial information.     

Effects of telencephalic ablation on habituation of arousal responses, within and between daily training sessions in goldfish

Goldfish Carassius auratus were presented with a moving shadow stimulus at 2-min intervals and their cardiac and ventilatory responses were monitored. Normal fish, fish with their telencephalon ablated, and those with sham operations were compared for responsiveness and habituation to repeatedly presented stimuli over the 3-day test period. While all groups showed increased habituation on successive days testing, fish with their telencephalon ablated showed significantly slower response habituation within the daily test sessions when compared with the control groups. Subjects with their telencephalon ablated also showed a tendency for increased responsiveness on initial stimulus presentation and poorer retention between days of information relating to the eliciting test stimulus.     

The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning.

The hypothesis that the noradrenergic projection from the locus coeruleus (LC) to the cerebral cortex and hippocampus is an important neural substrate for learning was evaluated. Maze performance was studied in rats receiving either electrolytic lesions of LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal tegmental noradrenergic projection. The LC lesions did not disrupt the acquisition of a running response for food reinforcement in an L-shaped runway, even though hippocampal-cortical norepinephrine (NE) was reduced to 29%. Greater telencephalic NE depletions (to 6% of control levels) produced by 6-OHDA also failed to disrupt the acquisition of this behavior or to impair the acquisition of a food-reinforced position habit in a T-maze. Neither locomotor activity nor habituation to a novel environment was affected by the 6-OHDA lesions. Rats with such lesions were, however, found to be significantly more distractible than were controls during the performance of a previously trained response. The hypothesis that telencephalic NE is of fundamental importance in learning was not supported. The data suggest that this system may participate in attentional mechanisms.     

Role of CA3 and CA1 subregions of the dorsal hippocampus on temporal processing of objects

Previous research in the dorsal CA1 and dorsal CA3 subregions of the hippocampus has been shown to play an important role in mediating temporal order memory for spatial location information. What is not known is whether the dorsal CA3 and dorsal CA1 subregions of the hippocampus are also involved in temporal order for visual object information. Rats with dorsal CA1, dorsal CA3 or control lesions were tested in a temporal order task for visual objects using an exploratory paradigm. The results indicated that the controls and the dorsal CA3 lesioned rats preferred the first rather then the last object they had explored previously, indicating good memory for temporal order of object presentation. In contrast, rats with dorsal CA1 lesions displayed a profound deficit in remembering the order of the visual object presentations in that they preferred the last object rather than the first. All three groups of rats preferred a novel object compared to a previously explored object suggesting normal detection of visual object novelty. The results suggest that only the dorsal CA1, but not dorsal CA3, region is critical for processing temporal information for visual objects without affecting the detection of new visual objects.     

Intrasession and intersession habituation in mice: From inbred strain variability to linkage analysis

When placed in a novel environment, mice tend to explore for a period of time, and then reduce the level of exploration. This reduction in locomotor or exploratory behavior is known as habituation and can occur within a single session or across sessions, respectively, termed intrasession and intersession habituation. Recent research indicates that there is a genetic component to habituation behavior and that some of the genes involved differ between the two types of habituation. The genetic evidence also suggests that intrasession habituation and intersession habituation are measuring somewhat different conceptual entities and with more such evidence may eventually help us understand the different pathways involved. Some of the genetic methods and tools used to unravel the roles of specific genes in both types of habituation are outlined here, with examples from the literature, as well as new data, to illustrate that this seemingly simple behavior is actually very complicated in terms of genetics. Evidence to date suggests that a number of genetic regions play roles in one or both types of habituation, and further research will be necessary to determine the specific genes involved.     

Decreased locomotor and investigatory exploration after denervation of catecholamine terminal fields in the forebrain of rats.

Exploratory behaviors were examined after bilateral microinjections of 6-hydroxydopamine into two hypothalamic sites that produced different patterns of denervation of forebrain catecholamine terminal fields. After anterolateral injections rats locomoted and reared less in a novel open field, responded abnormally to changes in the degree of novelty of the open field, and investigated a novel object less. These are deficits in exploratory behavior because they were not secondary to the inhibition of open-field behavior by hyperemotionality, by general motor disability, or by the failure to detect novel spaces or objects. Such anterolateral injections produced loss of catecholamine fibers, determined histochemically, in neocortical, hippocampal, anterolateral hypothalamic, mesolimbic, mesocortical, and anteromedioventral striatal terminal fields and loss of dopaminergic perikarya in the A10 and anteromedial A9 cell groups. No deficits in exploratory behaviors occurred, however, after bilateral anteromedial 6-hydroxydopamine injections that denervated neocortical, hippocampal, and anteromedial hypothalamic catecholamine terminal fields. A critical forebrain catecholaminergic innervation for exploratory responses to novel stimuli may be within areas that were denervated by anterolateral but not by anteromedial hypothalamic 6-nydroxydopamine injections. These areas are mesolimbic, mesocortical, anteromedioventral, and anterolateral hypothalamic terminal fields.     

Competitive short-term and long-term memory processes in spatial habituation

Exposure to a spatial location leads to habituation of exploration such that, in a novelty preference test, rodents subsequently prefer exploring a novel location to the familiar location. According to Wagner's (1981) theory of memory, short-term and long-term habituation are caused by separate and sometimes opponent processes. In the present study, this dual-process account of memory was tested. Mice received a series of exposure training trials to a location before receiving a novelty preference test. The novelty preference was greater when tested after a short, rather than a long, interval. In contrast, the novelty preference was weaker when exposure training trials were separated by a short, rather than a long interval. Furthermore, it was found that long-term habituation was determined by the independent effects of the amount of exposure training and the number of exposure training trials when factors such as the intertrial interval and the cumulative intertrial interval were controlled. A final experiment demonstrated that a long-term reduction of exploration could be caused by a negative priming effect due to associations formed during exploration. These results provide evidence against a single-process account of habituation and suggest that spatial habituation is determined by both short-term, recency-based memory and long-term, incrementally strengthened memory.     

Interspecific aggression and reactivity in rats: Effects of selective raphe lesions and additional olfactory bulb ablation

Large depletion of brain 5 HT has been shown to induce mouse-killing behavior in the rat. Selective lesions of the raphe nuclei have been investigated in order to determine whether the various components of the 5 HT system exert some specific control over this aggressive behavior. Electrolytic lesions of the dorsal or the median raphe nucleus do not induce mouse killing, whereas combined lesions of these nuclei elicit this behavior in about 40% of naive rats. Consequently, it appears that serotonergic neurons originating in the dorsal and median raphe nuclei work synergistically in mediating inhibitory control over mouse-killing behavior. Loco-motor activity is increased in novel environments by each of the selective lesions and to a larger extent by combined raphe lesions; 24 hours activity in resting conditions is unchanged during the light period, and increased during the dark period of the daily cycle by the various lesions. As it has been shown previously that hyper-activity in response to novelty following raphe lesions is not directly related to the 5 HT decrease in the brain, it appears that interspecific aggression and motor responsiveness must not be dependent on the same neural substrate within the raphe nuclei. The raphe lesions do not facilitate the elicitation of mouse killing by further olfactory bulb ablations, in contrast to earlier results where bulbectomy facilitated the induction of this behavior by raphe lesions.     

The influence of novelty and complexity on exploratory behavior in 12-month-old infants

This study investigated the influence of the novelty of the environment and the novelty and complexity of the objects (toys) it contained on the exploratory behavior of 12-month-old infants. Each infant was given a choice between novel and familiar toys located in two adjacent rooms (toy rooms). The novelty of the objects was manipulated by allowing the infants to play with one set of toys during a 5-min familiarization trial prior to the choice trial. The novetly of the environment was manipulated by allowing some infants to see, enter, and remain in the toy rooms during the familiarization trial. Finally, the complexity of the objects was manipulated by varying the number of familiar and novel toys; some Ss had four toys in each set (complex array) and some had only one (simple array). The results indicate that all three factors influenced the infants' exploratory behavior. Ss first approached, and spent more time manipulating, the novel than the familiar toys; they spent more time in the toy rooms if they were novel; and they spent more time manipulating the complex array of toys than the simple array.     

Effects of voluntary wheel running on heart rate, body temperature, and locomotor activity in response to acute and repeated stressor exposures in rats

Stress often negatively impacts physical and mental health but it has been suggested that voluntary physical activity may benefit health by reducing some of the effects of stress. The present experiments tested whether voluntary exercise can reduce heart rate, core body temperature and locomotor activity responses to acute (novelty or loud noise) or repeated stress (loud noise). After 6 weeks of running-wheel access, rats exposed to a novel environment had reduced heart rate, core body temperature, and locomotor activity responses compared to rats housed under sedentary conditions. In contrast, none of these measures were different between exercised and sedentary rats following acute 30-min noise exposures, at either 85 or 98 dB. Following 10 weeks of running-wheel access, both groups displayed significant habituation of all these responses to 10 consecutive daily 30-min presentations of 98 dB noise stress. However, the extent of habituation of all three responses was significantly enhanced in exercised compared to sedentary animals on the last exposure to noise. These results suggest that in physically active animals, under some conditions, acute responses to stress exposure may be reduced, and response habituation to repeated stress may be enhanced, which ultimately may reduce the negative and cumulative impact of stress.     

Fimbria-fornix lesions disrupt the dead reckoning (homing) component of exploratory behavior in mice

Exploration is the primary way in which rodents gather information about their spatial surroundings. Thus, spatial theories propose that damage to the hippocampus, a structure thought to play a fundamental role in spatial behavior, should disrupt exploration. Exploration in rats is organized. The animals create home bases that are central to exploratory excursions and returns, and hippocampal formation damage alters the organization of exploration by disrupting returns. Mice do not appear to readily establish home bases in novel environments, thus, for this species, it is more difficult to establish the contribution of the hippocampus to exploration. The purpose of the present study was threefold: develop a task in which mice center their exploration from a home base, determine whether the exploratory behavior is organized, and evaluate the role of fimbria-fornix lesions on exploration. Mice were given a novel exploratory task in which their nesting material was placed on a large circular table. Video records of control and fimbria-fornix mice were made in both light and dark (infrared light) conditions. Exploration patterns (outward trips, stops, and homeward trips) were reconstructed from the video records. Control mice centered their activity on their bedding, from which they made circuitous outward trips marked by many stops, and periodic direct returns. The bedding-centered behavior and outward trips of the fimbria-fornix mice were similar to those of the control mice, but significantly fewer direct return trips occurred. The direct homeward trips observed under light and dark conditions were consistent with a dead-reckoning strategy, in which an animal computes its present position and homeward trajectory from self-movement cues generated on the outward trip. Because the fimbria-fornix lesions disrupted the homeward component of exploratory trips, we conclude that the fimbria-fornix may contribute to dead reckoning in mice. The results also show that the home-bedding methodology facilitates the establishment of a home base by mice, thus providing a useful methodology for studies with mice.     

Habituation of exploratory activity to new stimuli, to the absence of a previously presented stimulus and to new contexts, in rats

Rats trained to run a shuttle-alleyway for food exhibited exploratory behaviour to a novel visual/tactual stimulus presented in a specific place of the alley. Intermittent presentation of the same stimulus in the same place resulted in reduction of the exploratory activity (habituation), both within and between sessions. The animals also directed exploratory activity to the absence of the previously presented stimulus at the place where the stimulus had been presented before; this latter response also habituated. The presentation (1) of the same stimulus to which the animals had already habituated in another place in the alleyway or when the animals were running in an opposite direction to the previous trials of stimulus presentation, or (2) of another stimulus, resulted, again, in the appearance of exploratory activity. These results lead to the conclusion that the animals code external events, store this information, and use it to detect spatial- and directional-contextual changes and to generate predictions about that specific environment.     

Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts

Rats have a natural tendency to spend more time exploring novel objects than familiar objects, and this preference can be used as an index of object recognition. Rats also show an exploratory preference for objects in locations where they have not previously encountered objects (an index of place memory) and for familiar objects in contexts different from those in which the objects were originally encountered (an index of context memory). In this experiment, rats with cytotoxic lesions of the hippocampal formation were tested on all three versions of the novelty-preference paradigm, with a 5-min retention interval between the familiarization and test phases. Rats with sham lesions displayed a novelty preference on all three trial types, whereas the rats with hippocampal lesions displayed a novelty preference on Object trials but did not discriminate between the objects on Place trials or Context trials. The findings indicate that hippocampal damage impairs memory for contextual or spatial aspects of an experience, whereas memory for objects that were part of the same experience are left relatively intact.     

Manual cyclical activity as an exploratory tool in neonates

Haptic texture perception was investigated in 3-day-old infants. Following a habituation sequence with a smooth or granular object, babies received a haptic test during which they held either the familiar or a new textured object. Two dependent measures were recorded: (1) Holding time was used to assess habituation as well as reaction to novelty and (2) hand pressure frequency exerted on the object was used to investigate neonates’ capacity to adjust their manipulation to the texture of objects. Both measures revealed neonates’ capacity to haptically perceive the texture of objects. From the results, it can be concluded that neonate’s manual cyclical activity recorded by HPF is a primary exploratory tool that is both necessary and sufficient to obtain knowledge about texture.     

新颖寻求特质对药物成瘾易感性的影响及其机制

新颖寻求特质是个体对新颖刺激或潜在的奖赏线索表现出愉悦或兴奋的先天倾向, 并且这种先天倾向会导致个体为寻求潜在的奖赏进行频繁的探索性活动。众多研究表明, 新颖寻求水平高的个体药物成瘾易感性高。多巴胺、5-羟色胺、谷氨酸、γ-氨基丁酸、胆囊收缩素、成纤维细胞生长因子及皮质酮可能参与了新颖寻求特质影响药物成瘾易感性的过程。未来, 仍需对新颖寻求特质影响药物成瘾易感性的神经生物学机制进行深入研究。     

Behavioral characterization of a transection of dorsal CA3 subcortical efferents: comparison with scopolamine and physostigmine infusions into dorsal CA3

Cholinergic projections from the medial septum and diagonal band of Broca into the hippocampus have long been implicated in learning and memory. Projections from CA3 to neurons in the medial septum and the diagonal band of Broca have been anatomically characterized. The present experiments were designed to evaluate interactions between the dorsal CA3 subcortical efferents and the cholinergic efferents from the medial septum and diagonal band of Broca for spatial and nonspatial (visual object) novelty detection in the rat. In Experiment 1, physostigmine and scopolamine (both 0.4 microL at 30 microM) were infused into dorsal CA3 and animals were tested on a spatial and nonspatial (visual object) novelty detection paradigm. Scopolamine infusions into dorsal CA3 caused deficits for both spatial and nonspatial (visual object) novelty detection. Physostigmine infusions into dorsal CA3 enhanced both spatial and nonspatial (visual object) novelty detection. These data support models proposing that acetylcholine may control the dynamics for encoding, consolidation, and retrieval in the hippocampus. In Experiment 2, a selective transection of dorsal CA3 efferents in the fimbria resulted in deficits for spatial and nonspatial (visual object) novelty detection. These deficits were similar to the deficits caused by scopolamine infusions into dorsal CA3. These data demonstrate that dorsal CA3 and the medial septum/diagonal band of Broca interact, and that dorsal CA3 influences cholinergic inputs into the hippocampus to facilitate encoding.