David I. G. Wilson

Lateral Entorhinal Cortex is Critical for Novel Object-Context Recognition

Episodic memory incorporates information about specific events or occasions including spatial locations and the contextual features of the environment in which the event took place. It has been modeled in rats using spontaneous exploration of novel configurations of objects, their locations, and the contexts in which they are presented. While we have a detailed understanding of how spatial location is processed in the brain relatively little is known about where the nonspatial contextual components of episodic memory are processed. Initial experiments measured c‐fos expression during an object‐context recognition (OCR) task to examine which networks within the brain process contextual features of an event. Increased c‐fos expression was found in the lateral entorhinal cortex (LEC; a major hippocampal afferent) during OCR relative to control conditions. In a subsequent experiment it was demonstrated that rats with lesions of LEC were unable to recognize object‐context associations yet showed normal object recognition and normal context recognition. These data suggest that contextual features of the environment are integrated with object identity in LEC and demonstrate that recognition of such object‐context associations requires the LEC. This is consistent with the suggestion that contextual features of an event are processed in LEC and that this information is combined with spatial information from medial entorhinal cortex to form episodic memory in the hippocampus.

Bar pressing for food: differential consequences of lesions to the anterior versus posterior pedunculopontine

The pedunculopontine tegmental nucleus (PPTg) is in a key position to participate in operant reinforcement via its connections with the corticostriatal architecture and the medial reticular formation. Indeed, previous work has demonstrated that rats bearing lesions of the whole PPTg are impaired when learning to make two bar presses for amphetamine reinforcement. Anterior and posterior portions of the PPTg make different anatomical connections, including preferential projections by the anterior PPTg to substantia nigra pars compacta dopamine neurons and by the posterior PPTg to ventral tegmental area dopamine neurons. We wanted to assess the effects of anterior and posterior PPTg ibotenate lesions on rats learning simple and more complex schedules of natural reinforcement. We trained rats with lesions to the anterior PPTg (n = 11) and the posterior PPTg (n = 5) [and appropriate controls (n = 15)] to bar press for food on a variety of fixed‐ratio and variable‐ratio reinforcement schedules and then during extinction. We found that posterior PPTg‐lesioned rats bar pressed at lower rates, were slower to learn to bar press, and often had deficits characteristic of impaired learning and/or motivation. In contrast, anterior PPTg‐lesioned rats learned to bar press for reinforcement at normal rates. However, they made errors of perseveration and anticipation throughout many schedules, and pressed at a higher rate than controls during extinction, deficits best characterized as reflecting disorganized response control. Together, these data suggest that the anterior PPTg and posterior PPTg (and their related circuits) contribute differently to reinforcement learning, incentive motivation, and response control, processes that are considered to malfunction in drug addiction.

Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory

The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual details of episodic memory. Combined with spatial information from the medial entorhinal cortex it is hypothesised that this contextual information is used to form an integrated spatially selective, context‐specific response in the hippocampus that underlies episodic memory. Recently, we reported that the LEC is required for recognition of objects that have been experienced in a specific context (Wilson et al. (2013) Hippocampus 23:352‐366). Here, we sought to extend this work to assess the role of the LEC in recognition of all associative combinations of objects, places and contexts within an episode. Unlike controls, rats with excitotoxic lesions of the LEC showed no evidence of recognizing familiar combinations of object in place, place in context, or object in place and context. However, LEC lesioned rats showed normal recognition of objects and places independently from each other (nonassociative recognition). Together with our previous findings, these data suggest that the LEC is critical for associative recognition memory and may bind together information relating to objects, places, and contexts needed for episodic memory formation.

Updating of action–outcome associations is prevented by inactivation of the posterior pedunculopontine tegmental nucleus

Highlights • The pedunculopontine tegmental nucleus is essential for action–outcome learning.• Sensitivity to instrumental contingency degradation is blocked by PPTg inactivation.• Inactivation of PPTg does not change performance of previously learnt operant tasks.• This is the first demonstration of a role for brainstem in action–outcome learning.• Learning functions of basal ganglia extend into the deepest parts of the circuitry.

Nucleus accumbens neurons in the rat exhibit differential activity to conditioned reinforcers and primary reinforcers within a second‐order schedule of saccharin reinforcement

The nucleus accumbens has been associated with processing information related to primary reinforcement and reward. Most neurophysiological studies report that nucleus accumbens neurons are phasically excited in response to the onsets of salient events during the seeking of reinforcement and to the delivery of primary reinforcers. However, a minority of studies report inhibition during primary reinforcement. We recorded from 65 neurons in the nucleus accumbens whilst thirsty rats performed under a second‐order schedule of saccharin reinforcement. This allowed us to analyse neural activity and behaviour during reinforcer‐seeking in the presence of conditioned reinforcers (second‐order stimuli, also called ‘conditioned stimuli’), and during primary reinforcer consumption. Specifically, we sought to examine the valence of potential neural responses to primary reinforcement, to compare these responses to second‐order stimulus‐evoked responses, and to determine whether responses were differential to second‐order stimuli presented at different time points within the schedule. Fifty out of 65 neurons we sampled responded to the second‐order stimulus and/or consumption of the primary reinforcer. Most neurons in our sample exhibited excitation following the second‐order stimulus and inhibition to the primary reinforcer, a pattern also present over the average response of the neural population. However, there was no systematic variation in neural responses evoked by second‐order stimuli presented at different temporal proximities to primary reinforcement. Our results provide evidence that partially overlapping mechanisms within the nucleus accumbens differentially process conditioned reinforcers and primary reinforcers.

Subcortical Connections of the Basal Ganglia

Chapter describing subcortial connections of the Basal Ganglia. The Basal Ganglia comprise a group of forebrain nuclei that are interconnected with the cerebral cortex, thalamus and brainstem. Basal ganglia circuits are involved in various functions, including motor control and learning, sensorimotor integration, reward and cognition. The importance of these nuclei for normal brain function and behavior is emphasized by the numerous and diverse disorders associated with basal ganglia dysfunction, including Parkinson’s disease, Tourette’s syndrome, Huntington’s disease, obsessive-compulsive disorder, dystonia, and psychostimulant addiction.

On the relationships between the pedunculopontine tegmental nucleus, corticostriatal architecture and the medial reticular formation

Recent studies have established that the pedunculopontine tegmental nucleus (PPTg) is integrated into corticostriatal looped architecture through connections that include established basal ganglia output nuclei (pallidum, subthalamus and substantia nigra pars reticulata), thalamus and midbrain dopamine (DA) containing neurons in both the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). It is becoming apparent that the PPTg can be functionally dissociated internally. A simple dissociation is between posterior and anterior PPTg. The posterior PPTg contains a large proportion of cholinergic neurons, has polymodal sensory input that triggers very fast neuronal activity and projects preferentially to the VTA. In contrast, the anterior PPTg contains fewer cholinergic neurons, receives outflow from both corticostriatal systems and the extended amygdala and projects to the SNC. We suggest that this organization maps on to the spiral corticostriatal architecture such that the posterior PPTg interacts with ventromedial striatal systems (a proposed function of which is to integrate incentive salient stimuli to shape flexible goal-directed actions), whereas the anterior PPTg interacts with dorsolateral striatal circuits (which are thought to mediate the learning and execution of stimulus–response associations and the formation of habits). By these interactions, the PPTg en masse contributes to high-order decision making processes that shape action selection. In addition to this we also suggest that the PPTg integrates with medial reticular formation systems that operate as an immediate low-level action selection mechanism. We hypothesize that the PPTg has a pivotal position, bridging between higher order action selection mechanisms dealing with flexible learning of novel action patterns and lower level action selection processes that permit very fast responding to imperative stimuli.

Neurons in dopamine‐rich areas of the rat medial midbrain predominantly encode the outcome‐related rather than behavioural switching properties of conditioned stimuli

Midbrain dopamine neurons are phasically activated by a variety of sensory stimuli. It has been hypothesized that these activations contribute to reward prediction or behavioural switching. To test the latter hypothesis we recorded from 131 single neurons in the ventral tegmental area and retrorubral field of thirsty rats responding during a modified go/no‐go task. One‐quarter (n = 33) of these neurons responded to conditioned stimuli in the task, which varied according to the outcome with which they were associated (saccharin or quinine solution) and according to whether they triggered a switch in the ongoing sequence of the animals behaviour (‘behavioural switching’). Almost half the neurons (45%) responded differentially to saccharin‐ vs. quinine‐conditioned stimuli; the activity of a minority (15%) correlated with an aspect of behavioural switching (mostly exhibiting changes from baseline activity in the absence of a behavioural switch) and one‐third (33%) encoded various outcome–switch combinations. The strongest response was excitation to the saccharin‐conditioned stimulus. Additionally, a proportion (38%) of neurons responded during outcome delivery, typically exhibiting inhibition during saccharin consumption. The neurons sampled did not fall into distinct clusters on the basis of their electrophysiological characteristics. However, most neurons that responded to the outcome‐related properties of conditioned stimuli had long action potentials (> 1.2 ms), a reported characteristic of dopamine neurons. Moreover, responses to saccharin‐conditioned stimuli were functionally akin to dopamine responses found in the macaque and rat nucleus accumbens responses observed within the same task. In conclusion, our data are more consistent with the reward‐prediction than the behavioural switching hypothesis.