Contextual fear conditioning emerges around post-natal day (PD) 23 in the rat. This is thought to reflect hippocampus-dependent conjunctive learning, which binds the individual features of the context into a unified representation (Rudy, 1993). However, context conditioning can also be supported by hippocampus-independent, feature-based simple associations (Rudy, 2009) and these may operate at PD23–24 (Pugh & Rudy, 1996). To address this issue, we studied the ontogeny of a variant of contextual fear conditioning, termed the context-preexposure-facilitation-effect (CPFE), in which exposure to context and (immediate) foot shock occur on successive occasions. This variant requires conjunctive as opposed to feature-based simple associations (Rudy, 2009). We tested PD17, 24, and 31 rats on the CPFE vs. conventional context conditioning (Exp. 1) and on the CPFE with stronger reinforcement (Exp. 2). The CPFE emerged on PD24 regardless of reinforcer strength and in parallel with context conditioning. Infusions of the NMDA antagonist, MK-801, into the dorsal hippocampus just before preexposure on PD24 eliminated the CPFE, whereas infusions occurring after preexposure had no effect (Exp. 3). These findings demonstrate a role of hippocampal NMDA receptors in the CPFE as early as PD24 and implicate conjunctive learning mechanisms in the ontogeny of contextual fear conditioning.

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which context learning and context-shock associations occur on separate occasions. The CPFE with an immediate shock emerges between Postnatal Day (PND) 17 and 24 in the rat and depends on hippocampal NMDA-receptor function in PND 24 rats (Schiffino et al., 2011). This study investigated this ontogenetic effect further and reports three findings: First, the CPFE is absent on PND19 but emerges modestly in rats given exposure on PND 21. Second, the absence of the CPFE on PND17 does not reflect inability to consolidate the context-shock association established on the training day. Lastly, the CPFE on PND 24 requires exposure to the combined features of the context. These results are the first to show that the early development of contextual fear conditioning depends on conjunctive representations and that processes underlying the CPFE begin to emerge around PND 21 in the rat.

Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: sham-intubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning.

Within most contemporary learning theories, reinforcement prediction error, the difference between the obtained and expected reinforcer value, critically influences associative learning. In some theories, this prediction error determines the momentary effectiveness of the reinforcer itself, such that the same physical event produces more learning when its presentation is surprising than when it is expected. In other theories, prediction error enhances attention to potential cues for that reinforcer by adjusting cue-specific associability parameters, biasing the processing of those stimuli so that they more readily enter into new associations in the future. A unique feature of these latter theories is that such alterations in stimulus associability must be represented in memory in an enduring fashion. Indeed, considerable data indicate that altered associability may be expressed days after its induction. Previous research from our laboratory identified brain circuit elements critical to the enhancement of stimulus associability by the omission of an expected event, and to the subsequent expression of that altered associability in more rapid learning. Here, for the first time, we identified a brain region, the posterior parietal cortex, as a potential site for a memorial representation of altered stimulus associability. In three experiments using rats and a serial prediction task, we found that intact posterior parietal cortex function was essential during the encoding, consolidation, and retrieval of an associability memory enhanced by surprising omissions. We discuss these new results in the context of our previous findings and additional plausible frontoparietal and subcortical networks.

Most modern theories of associative learning emphasize a critical role for prediction error (PE, the difference between received and expected events). One class of theories, exemplified by the Rescorla-Wagner (1972) model, asserts that PE determines the effectiveness of the reinforcer or unconditioned stimulus (US): surprising reinforcers are more effective than expected ones. A second class, represented by the Pearce-Hall (1980) model, argues that PE determines the associability of conditioned stimuli (CSs), the rate at which they may enter into new learning: the surprising delivery or omission of a reinforcer enhances subsequent processing of the CSs that were present when PE was induced. In this mini-review we describe evidence, mostly from our laboratory, for PE-induced changes in the associability of both CSs and USs, and the brain systems involved in the coding, storage and retrieval of these altered associability values. This evidence favors a number of modifications to behavioral models of how PE influences event processing, and suggests the involvement of widespread brain systems in animals’ responses to PE.

Neonatal alcohol exposure impairs cognition and learning in adulthood and permanently damages the hippocampus. Wheel running (WR) improves hippocampus-associated learning and memory and increases the genesis and survival of newly generated neurons in the hippocampal dentate gyrus. WR significantly increases proliferation of newly generated dentate granule cells in alcohol-exposed (AE) and control rats on Postnatal Day (PD) 42 but only control rats show an increased number of surviving cells thirty days after WR (Helfer et al., 2009b). The present studies examined whether proliferation-promoting WR followed by survival-enhancing environmental complexity (EC) during adolescence could increase survival of new neurons in AE rats. On PD4–9, pups were intubated with alcohol in a binge-like manner (5.25g/kg/day, AE), were sham-intubated (SI), or were reared normally (suckle control, SC). On PD30 animals were assigned to WR (PD30–42) followed by EC (PD42–72; WR/EC) or were socially housed (SH/SH) for the duration of the experiment. All animals were injected with 200 mg/kg BrdU on PD41. In Experiment 1, survival of newly generated cells was significantly enhanced in the AE-WR/EC group in comparison with AE-SH/SH group. Experiment 2A examined trace eyeblink conditioning. In the SH/SH condition, AE impaired trace eyeblink conditioning relative to SI and SC controls. In the WR/EC condition, AE rats performed as well as controls. In Experiment 2B, the same intervention was examined using the context preexposure facilitation effect (CPFE); a hippocampus-dependent variant of contextual fear conditioning. Again, the WR/EC intervention reversed the deficit in conditioned fear to the context that was evident in the SH/SH condition. Post-weaning environmental manipulations promote cell survival and reverse learning deficits in rats that were exposed to alcohol during development. These manipulations may provide a basis for developing interventions that ameliorate learning impairments associated with human fetal alcohol spectrum disorders.

Increases in broadband cortical electroencephalogram (EEG) power in the gamma band (30–80 Hz) range have been observed in schizophrenia patients and in mouse models of schizophrenia. They are also seen in humans and animals treated with the psychotomimetic agent ketamine. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. Here we report that tonic optogenetic manipulation of an ascending arousal system bi-directionally tunes cortical broadband gamma power, allowing on-demand tests of the effect on cortical processing and behavior. Constant, low wattage optogenetic stimulation of basal forebrain (BF) neurons containing the calcium-binding protein parvalbumin (PV) increased broadband gamma frequency power, increased locomotor activity, and impaired novel object recognition. Concomitantly, task-associated gamma band oscillations induced by trains of auditory stimuli, or exposure to novel objects, were impaired, reminiscent of findings in schizophrenia patients. Conversely, tonic optogenetic inhibition of BF-PV neurons partially rescued the elevated broadband gamma power elicited by subanesthetic doses of ketamine. These results support the idea that increased cortical broadband gamma activity leads to impairments in cognition and behavior and identify BF-PV activity as a modulator of this activity. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The current experiments adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that NMDA receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat.