Stephan G. Anagnostaras

Hippocampus and Contextual Fear Conditioning: Recent Controversies and Advances

Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired contextual fear without impairing memory of discrete training stimuli, i.e., DH lesions produce an anterograde and time‐limited retrograde amnesia specific to contextual memory. These data are consistent with the standard model which posits temporary involvement of the hippocampus in recent memory maintenance. However, three recent controversies apparently weaken the case for a selective mnemonic role for the hippocampus in contextual fear. First, although retrograde amnesia (from posttraining lesions) is severe, anterograde amnesia (from pretraining lesions) may be mild or nonexistent. Second, a performance, rather than mnemonic, account of contextual freezing deficits in hippocampal‐lesioned animals has been offered. Third, damage to the entire hippocampus, including the ventral hippocampus, can produce a dramatic and temporally stable disruption of context and tone fear. These data are reviewed and explanations are offered as to why they do not necessarily challenge the standard model of hippocampal memory function in contextual fear. Finally, a more complete description of the hippocampus proposed role in contextual fear is offered, along with new data supporting this view. In summary, the data support a specific mnemonic role for the DH in the acquisition and consolidation of contextual representations. Hippocampus 2001;11:8–17.

Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice

Blockade of cholinergic neurotransmission by muscarinic receptor antagonists produces profound deficits in attention and memory. However, the antagonists used in previous studies bind to more than one of the five muscarinic receptor subtypes. Here we examined memory in mice with a null mutation of the gene coding the M1 receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain. In contrast with previous studies using nonselective pharmacological antagonists, the M1 receptor deletion produced a selective phenotype that included both enhancements and deficits in memory. Long-term potentiation (LTP) in response to theta burst stimulation in the hippocampus was also reduced in mutant mice. M1 null mutant mice showed normal or enhanced memory for tasks that involved matching-to-sample problems, but they were severely impaired in non-matching-to-sample working memory as well as consolidation. Our results suggest that the M1 receptor is specifically involved in memory processes for which the cortex and hippocampus interact.

Mice Lacking the β3 Subunit of the GABAA Receptor Have the Epilepsy Phenotype and Many of the Behavioral Characteristics of Angelman Syndrome

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11–13. The genes in 15q11–13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor β3subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest–activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.

Role of the Basolateral Amygdala in the Storage of Fear Memories across the Adult Lifetime of Rats

The basolateral amygdala (BLA) is intimately involved in the development of conditional fear. Converging lines of evidence support a role for this region in the storage of fear memory but do not rule out a time-limited role in the memory consolidation. To examine this issue, we assessed the stability of BLA contribution to fear memories acquired across the adult lifetime of rats. Fear conditioning consisted of 10 tone–shock pairings in one context (remote memory), followed 16 months later by 10 additional tone–shock pairings with a novel tone in a novel context (recent memory). Twenty-four hours after recent training, rats were given NMDA or sham lesions of the BLA. Contextual and tone freezing were independently assessed in individual test sessions. Sham-lesioned rats showed high and comparable levels of freezing across all context and tone tests. In contrast, BLA-lesioned rats displayed robust freezing deficits across both recent and remote tests. Subsequent open-field testing revealed no effects of BLA lesions on activity patterns in a dark open field or during bright light exposure. Lesioned rats were able to reacquire normal levels of context-specific freezing after an overtraining procedure (76 unsignaled shocks). Together, these findings indicate that BLA lesions do not disrupt freezing behavior by producing hyperactivity, an inability to suppress behavior, or an inability to freeze. Rather, the consistent pattern of freezing deficits at both training-to-lesion intervals supports a role for the BLA in the permanent storage of fear memory.

Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning.

The authors investigated the influence of associative pairing of contextual stimuli with amphetamine administration on the expression of psychomotor sensitization. Animals received d-amphetamine or saline in group-specific environments. Amphetamine produced robust behavioral sensitization in all environments, but when an amphetamine challenge was given in a test environment that was novel for some groups but not others, the expression of sensitization was completely context specific. An injection of saline in the amphetamine-paired environment produced a conditional response (CR), but this was quite small compared to the magnitude of the sensitized response, and sensitization remained completely context specific following extinction of the CR. Results are discussed in relation to 3 models of how context may modulate the expression of sensitization: an excitatory conditioning model, an inhibitory conditioning model, and an occasion-setting model.

Context Fear Learning in the Absence of the Hippocampus

Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent past but do not always prevent new learning. To better understand this discrepancy, we thoroughly examined the acquisition of context fear in rats with pretraining excitotoxic lesions of the dorsal hippocampus. In the first experiment, animals received a shock immediately after placement in the context or after variable delays. Immediate shock produced no context fear learning in lesioned rats or controls. In contrast, delayed shock produced robust context fear learning in both groups. The absence of fear with immediate shock occurs because animals need time to form a representation of the context before shock is presented. The fact that it occurs in both sham and lesioned rats suggests that they learn about the context in a similar manner. However, despite learning about the context in the delay condition, lesioned rats did not acquire as much fear as controls. The second experiment showed that this lesion-induced deficit could be overcome by increasing the number of conditioning trials. Lesioned animals learned normally after multiple shocks, regardless of freezing level or trial spacing. The last experiment showed that animals with complete hippocampus lesions could also learn about the context, although the same lesions produced devastating retrograde amnesia. These results demonstrate that alternative systems can acquire context fear but do so less efficiently than the hippocampus.

The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment

Two experiments were designed to assess the effect of a “novel” environment on the development of sensitization to the psychomotor activating effects ofd-amphetamine. In the first experiment, rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system received ten daily injections of amphetamine (2 mg/kg), either in their home cages or in novel test cages. The home and novel cages were physically identical (cylindrical transparent buckets), but one group lived and were tested in these cages, whereas the other group was transported from the stainless steel hanging cages where they lived to these novel test cages, for each test session. The first injection of amphetamine produced significantly more rotational behavior in animals tested in a novel environment than in animals tested at home. In addition, animals tested in a novel environment showed greater sensitization than animals tested at home, so the difference between the two groups was even more pronounced following the last injection. In a second experiment, locomotor activity was quantified in rats that received ten injections of either saline or 1.5 mg/kg amphetamine, in their home cages or in a physically identical novel environment. Again, there was a significantly greater locomotor response to the first injection of amphetamine, and greater sensitization, in animals tested in a novel environment than in animals tested at home. These data indicate that environmental factors can exert a large effect on the susceptibility to sensitization, and mechanisms by which this may occur are discussed.

Memory Processes Governing Amphetamine-induced Psychomotor Sensitization

We investigated how, under certain circumstances, the expression of psychomotor sensitization comes to be context-specific. Rats that had previously sustained 6-hydroxydopamine-induced unilateral dopamine depletion received repeated injections of d-amphetamine (AMPH) or saline in group-specific environments, and rotational behavior was measured as an index of psychomotor activation. Following these treatments some groups were given electroconvulsive shock (ECS), when memories of the drug experience were reactivated (and therefore vulnerable to disruption), in order to produce retrograde amnesia. Animals given an AMPH challenge in the environment in which they received drug treatments (Paired) expressed robust sensitization. Animals given an AMPH challenge in a context that was never paired with drug administration (Unpaired) did not express sensitization. A saline challenge in the AMPH paired context produced a conditioned rotational response (CR). ECS had no effect in Control animals, no effect on the expression of sensitization in Paired animals, and no effect on the expression of the CR in Paired animals. However, ECS did affect Unpaired groups: unlike Unpaired animals given sham ECS, Unpaired animals given ECS expressed robust sensitization. Thus, without ECS, the expression of sensitization must have been suppressed in the Unpaired animals (who had the same drug history as Paired animals), and ECS released this otherwise suppressed sensitization. Based on these and other findings, we propose that three memory mechanisms regulate context-specificity of AMPH sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of non-associative learning; (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process we speculate may involve a form of inhibitory occasion-setting; (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected. It is suggested that the ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse.

The startled seahorse: is the hippocampus necessary for contextual fear conditioning?

are not known, although it is assumedthat configural strategies normally supersede elemental strategies.The lion’s share of work implicat-ing the hippocampus in contextualconditioning has been derived fromstudies of fear conditioning in rats. Infear conditioning tasks, discrete and/orcontextual CSs that are paired withfootshock come to evoke conditionalfear responses (CRs) such as defecation,potentiated acoustic startle, elevatedblood pressure and freezing. In manylaboratories, contextual fear is assessedby returning the rats to the condition-ing chamber and measuring freezing.That the hippocampus plays an impor-tant role in contextual fear condition-ing is indicated by studies demonstrat-ing that dorsal hippocampal lesionsattenuate freezing to contextual CSs,but do not alter freezing behavior todiscrete CSs (Refs 2,3). Hippocampal le-sions also impair contextual fear condi-tioning following unsignaled train-ing

An opportunistic theory of cellular and systems consolidation

Memories are often classified as hippocampus dependent or independent, and sleep has been found to facilitate both, but in different ways. In this Opinion, we explore the optimal neural state for cellular and systems consolidation of hippocampus-dependent memories that benefit from sleep. We suggest that these two kinds of consolidation, which are ordinarily treated separately, overlap in time and jointly benefit from a period of reduced interference (during which no new memories are formed). Conditions that result in reduced interference include slow wave sleep (SWS), NMDA receptor antagonists, benzodiazepines, alcohol and acetylcholine antagonists. We hypothesize that the consolidation of hippocampal-dependent memories might not depend on SWS per se. Instead, the brain opportunistically consolidates previously encoded memories whenever the hippocampus is not otherwise occupied by the task of encoding new memories.