Michael W. Shiflett

At the limbic-motor interface: disconnection of basolateral amygdala from nucleus accumbens core and shell reveals dissociable components of incentive motivation.

Although it has long been hypothesized that the nucleus accumbens (NAc) acts as an interface between limbic and motor regions, direct evidence for this modulatory role on behavior is lacking. Using a disconnection procedure in rats, we found that basolateral amygdala (BLA) input to the core and medial shell of the NAc separately mediate two distinct incentive processes controlling the performance of goal‐directed instrumental actions, respectively: (i) the sensitivity of instrumental responding to changes in the experienced value of the goal or outcome, produced by specific satiety‐induced outcome devaluation; and (ii) the effect of reward‐related cues on action selection, observed in outcome‐specific Pavlovian–instrumental transfer. These results reveal, therefore, that dissociable neural circuits involving BLA inputs to the NAc core and medial shell mediate distinct components of the incentive motivational processes controlling choice and decision‐making in instrumental conditioning.

Acquisition and performance of goal-directed instrumental actions depends on ERK signaling in distinct regions of dorsal striatum in rats

The performance of goal-directed actions relies on an animals previous knowledge of the outcomes or consequences that result from its actions. Additionally, a sensorimotor learning process linking environmental stimuli with actions influences instrumental performance by selecting actions for additional evaluation. These distinct decision-making processes in rodents depend on separate subregions of the dorsal striatum. Whereas the posterior dorsomedial striatum (pDMS) is required for the encoding of actions with their outcomes or consequences, the dorsolateral striatum (DLS) mediates action selection based on sensorimotor learning. However, the molecular mechanisms within these brain regions that support learning and performance of goal-directed behavior are not known. Here we show that activation of extracellular signal-regulated kinase (ERK) in the dorsal striatum has a critical role in learning and performance of instrumental goal-directed behavior in rodents. We observed an increase in p42 ERK (ERK2) activation in both the pDMS and DLS during both the acquisition and performance of recently acquired instrumental goal-directed actions. Furthermore, disruption of ERK activation in the pDMS prevented both the acquisition of action–outcome associations, as well as the performance of goal-directed actions guided by previously acquired associations, whereas disruption of ERK activation in the DLS disrupted instrumental performance but left instrumental action–outcome learning intact. These results provide evidence of a critical, region-specific role for ERK signaling in the dorsal striatum during the acquisition of instrumental learning and suggest that processes sensitive to ERK signaling within these striatal subregions interact to control instrumental performance after initial acquisition.

Seasonal changes in neuron numbers in the hippocampal formation of a food-hoarding bird: the black-capped chickadee.

The volume of the hippocampal formation (HF) in black-capped chickadees (Poecile atricapillus) varies across the seasons, in parallel with the seasonal cycle in food hoarding. In this study, we estimate cell density and total cell number in the HF across seasons in both juveniles and adults. We find that the seasonal variation in volume is due to an increase in the number of small and large cells (principally neurons) in the fall. Adults also have lower neuron densities than juveniles. Both juveniles and adults show an increase in cell density in the rostral part of the HF in August and a subsequent decrease toward October. This suggests that the net cell addition to the HF may already start in August. We discuss the implications of this early start with respect to the possibility that the seasonal change in HF volume is driven by the experience of food hoarding. We also speculate on the functional significance of the addition of neurons to the HF in the fall.

Molecular substrates of action control in cortico-striatal circuits

The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus-response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction.

Contributions of ERK signaling in the striatum to instrumental learning and performance.

The striatum is critical for learning and decision making; however, the molecular mechanisms that govern striatum function are not fully understood. The extracellular signal regulated kinase (ERK) cascade is an important signaling pathway that underlies synaptic plasticity, cellular excitability, learning and arousal. This review focuses on the role of ERK signaling in striatum function. ERK is activated in the striatum by coordinated dopamine and glutamate receptor signaling, where it underlies corticostriatal synaptic plasticity and influences striatal cell excitability. ERK activation in the dorsal striatum is necessary for action-outcome learning and performance of goal-directed actions. In the ventral striatum, ERK is necessary for the motivating effects of reward-associated stimuli on instrumental performance. Dysregulation of ERK signaling in the striatum by repeated drug exposure contributes to the development of addictive behavior. These results highlight the importance of ERK signaling in the striatum as a critical substrate for learning and as a regulator of ongoing behavior. Furthermore, they suggest that ERK may be a suitable target for therapeutics to treat disorders of learning and decision making that arise from compromised striatum function.

Cannabinoid inhibition improves memory in food-storing birds, but with a cost

Food–storing birds demonstrate remarkable memory ability in recalling the locations of thousands of hidden food caches. Although this behaviour requires the hippocampus, its synaptic mechanisms are not understood. Here we show the effects of cannabinoid receptor (CB1–R) blockade on spatial memory in food–storing black–capped chickadees (Poecile atricapilla). Intra–hippocampal infusions of the CB1–R antagonist SR141716A enhanced long–term memory for the location of a hidden food reward, measured 72 h after encoding. However, when the reward location changed during the retention interval, birds that had received SR141716A during initial learning showed impairments in recalling the most recent reward location. Thus, blocking CB1–R activity may lead to more robust, long–lasting memories, but these memories may be a source of proactive interference. The relationship between trace strength and interference may be important in understanding neural mechanisms of hippocampal function in general, as well as understanding the enhanced memory of food–storing birds.

Appetitive Pavlovian conditioned stimuli increase CREB phosphorylation in the nucleus accumbens.

The transcription factor cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc) has been shown to regulate an animals behavioral responsiveness to emotionally salient stimuli, and an increase in CREB phosphorylation in the NAc has been observed during exposure to rewarding stimuli, such as drugs of abuse. Here we show that CREB phosphorylation increases in the NAc also during exposure to cues that an animal has associated with delivery of natural rewards. Adult male Sprague-Dawley rats (rattus norvegicus) were trained to associate an auditory stimulus with delivery of food pellets, and CREB phosphorylation was examined in the striatum following training. We found that repeated tone-food pairings resulted in an increase in CREB phosphorylation in the NAc but not in the adjacent dorsal striatum or in the NAc 3h after the final training session. We further found that the cue itself, as opposed to the food pellets, the training context, or tone-food pairings, was sufficient to increase CREB phosphorylation in the NAc. These results suggest that the processing of primary rewarding stimuli and of environmental cues that predict them triggers similar accumbal signaling mechanisms.

The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD

Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD) have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75–P105] Spontaneously Hypertensive Rats (SHR; ADHD rat model) and Wistar–Kyoto rats (WKY), the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action–outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate (MPH), a commonly used ADHD medication, on goal-directed behavior, we injected rats with either MPH or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, MPH administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how MPH acts differently on SHR and WKY animals to restore or impair this behavior, respectively.

Dopaminergic Modulation of Goal-Directed Behavior in a Rodent Model of Attention-Deficit/Hyperactivity Disorder

Aside from its clinical symptoms of inattention, impulsivity and hyperactivity, patients with Attention/Deficit-Hyperactivity Disorder (ADHD) display reward and motivational impairments. These impairments may reflect a deficit in action control, that is, an inability to flexibly adapt behavior to changing consequences. We previously showed that spontaneously hypertensive rats (SHR), an inbred rodent model of ADHD, show impairments in goal-directed action control, and instead are predominated by habits. In this study, we examined the effects of specific dopamine receptor sub-type (D1 and D2) agonists and antagonists on goal-directed behavior in SHR and the normotensive inbred control strain Wistar-Kyoto (WKY) rats. Rats acquired an instrumental response for different-flavored food rewards. A selective-satiety outcome devaluation procedure followed by a choice test in extinction revealed outcome-insensitive habitual behavior in SHR rats. Outcome-sensitive goal-directed behavior was restored in SHR rats following injection prior to the choice test of the dopamine D2 receptor agonist Quinpirole or dopamine D1 receptor antagonist SCH23390, whereas WKY rats showed habitual responding following exposure to these drugs. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather is due to a misbalance between activation of dopamine D1 and D2 receptor pathways that govern action control.

Functions of Neuropilins in Wiring the Nervous System and Their Role in Neurological Disorders

The proper wiring of the nervous system depends on an orderly series of events, beginning in embryonic development with neuronal migration, axon and dendrite development, and guidance events and continuing in postnatal development with synaptogenesis, pruning of axonal projections, and synapse refinement. In the nervous system, neuropilins function mainly with the class 3 secreted semaphorins (Sema3s) to mediate a majority of these developmental processes. Neuropilins bind to Sema3s as obligatory cell surface co-receptors and form a complex with the type A plexin family members, as well as with cell adhesion molecules and other modulatory co-receptors, to activate intracellular signaling networks that, in most cases, influence cytoskeletal dynamics and neuronal morphology. Changes to neuronal morphology are known to regulate neural connectivity and activity. In this chapter we will focus on recent discoveries of neuropilin functions, mediated by Sema3 signaling, to regulate wiring of the nervous system. In addition, we will highlight some of the emerging roles neuropilins play in neurodevelopmental and neuropsychiatric disorders.