A neural model of hippocampal–striatal interactions in associative learning and transfer generalization in various neurological and psychiatric patients

Abstract

Building on our previous neurocomputational models of basal ganglia and hippocampal region function (and their modulation by dopamine and acetylcholine, respectively), we show here how an integration of these models can inform our understanding of the interaction between the basal ganglia and hippocampal region in associative learning and transfer generalization across various patient populations. As a common test bed for exploring interactions between these brain regions and neuromodulators, we focus on the acquired equivalence task, an associative learning paradigm in which stimuli that have been associated with the same outcome acquire a functional similarity such that subsequent generalization between these stimuli increases. This task has been used to test cognitive dysfunction in various patient populations with damages to the hippocampal region and basal ganglia, including studies of patients with Parkinson’s disease (PD), schizophrenia, basal forebrain amnesia, and hippocampal atrophy. Simulation results show that damage to the hippocampal region—as in patients with hippocampal atrophy (HA), hypoxia, mild Alzheimer’s (AD), or schizophrenia—leads to intact associative learning but impaired transfer generalization performance. Moreover, the model demonstrates how PD and anterior communicating artery (ACoA) aneurysm—two very different brain disorders that affect different neural mechanisms—can have similar effects on acquired equivalence performance. In particular, the model shows that simulating a loss of dopamine function in the basal ganglia module (as in PD) leads to slow acquisition learning but intact transfer generalization. Similarly, the model shows that simulating the loss of acetylcholine in the hippocampal region (as in ACoA aneurysm) also results in slower acquisition learning. We argue from this that changes in associative learning of stimulus–action pathways (in the basal ganglia) or changes in the learning of stimulus representations (in the hippocampal region) can have similar functional effects.

Introduction

As a common test bed for neurocomputational exploration of the interactions between the basal ganglia (and dopamine) and the hippocampal region (and acetylcholine), we focus on the acquired equivalence task, an associative learning paradigm in which stimuli that have been associated with the same outcome acquire a functional similarity such that subsequent generalization between these stimuli increases (Bondi et al., 1993, Grice and Davis, 1960). Both human neuropsychological (Bodi et al., 2009, Keri, Nagy, et al., 2005, Myers et al., 2003, Myers et al., 2008, Weiler et al., 2009) and animal lesion (Coutureau et al., 2002) studies show that both the hippocampal region and the basal ganglia are important for acquired equivalence.

The acquired equivalence task has two phases: acquisition (learning to associate two stimuli) and transfer generalization (learning that cues become equivalent when they were previously associated with the same response). Several neuropsychological studies from our lab have argued that the associative learning and transfer generalization processes rely on different neural structures (Myers et al., 2003, Myers et al., 2008): initial associative learning relies on the integrity of the basal ganglia, whereas transfer generalization relies on the integrity of the hippocampal region.

For example, patients with mild Alzheimer’s disease, hippocampal atrophy (HA), and hypoxia are impaired at the transfer generalization phase of the task (Bodi et al., 2009, Myers et al., 2003, Myers et al., 2008) (see Table 1). Mild Alzheimer’s disease is associated with dysfunction to the medial temporal lobe and hippocampal region (de Leon, George, Stylopoulos, Smith, & Miller, 1989). Similarly, hypoxic brain injury causes bilateral neuropathology of the hippocampus and associated medial temporal areas (Kesner & Hopkins, 2001). Recently, Di Paola et al. (2008) reported hippocampal dysfunction in hypoxic patients. These results suggest that the hippocampal region plays an important role in transfer generalization performance.

Keri et al. (2005) also found that schizophrenic patients are impaired at transfer generalization in the acquired equivalence task. These results were also confirmed in a recent study (Weiler et al., 2009). It is likely that impaired transfer generalization performance in schizophrenic patients is due to hippocampal dysfunction, which has been reported in the literature (Goldman and Mitchell, 2004, Goldman et al., 2007, Lodge and Grace, 2008, Spoletini et al., 2009). Schizophrenia is a psychiatric disorder which is mainly associated with positive symptoms (e.g., delusions and hallucinations) and negative symptoms (e.g., apathy). It has been shown that schizophrenic patients have mediotemporal lobe and hippocampal dysfunction (Bogerts et al., 1985, Boyer et al., 2007, Goldman and Mitchell, 2004, Heckers, 2001, Keri, 2008, Weinberger, 1999). Bogerts et al. (1985) also reported a decrease in hippocampal size but an intact basal ganglia structure in schizophrenic patients as seen in structural brain imaging. Schizophrenic patients also show declarative memory deficits, which suggest hippocampal region dysfunction (Aleman et al., 1999, Cirillo and Seidman, 2003). Lesioning the hippocampus in animals is also used as a model of schizophrenia (Tseng, Chambers, & Lipska, 2009). In addition, Rametti et al. (2009) reported decreased hippocampal activity in schizophrenic patients performing declarative memory tasks. Our model argues that hippocampal dysfunction is responsible for transfer generalization deficits in schizophrenic patients.

Unlike mild Alzheimer’s disease, schizophrenia, and hypoxia, patients with Parkinson’s disease and ACoA (anterior communicating artery) aneurysm are impaired at the acquisition phase of the acquired equivalence task. Parkinson’s disease is a neurodegenerative disorder associated with reduced dopamine levels in the basal ganglia (Jellinger, 1999, Kish et al., 1988). On the other hand, the ACoA is one of the most common sites of aneurysm in the brain. The ACoA sends projection to the prefrontal cortex and the basal forebrain (Wright, Boeve, & Malec, 1999), and an aneurysm to ACoA is found to affect basal forebrain functioning (Wright et al., 1999). Patients with ACoA aneurysm have basal forebrain damage, which affects cholinergic input to the hippocampus. Patients with ACoA aneurysm have amnesia (O’Connor & Lafleche, 2004), executive dysfunction (Simard, Rouleau, Brosseau, Laframboise, & Bojanowsky, 2003), and other cognitive deficits (Bondi et al., 1993, DeLuca, 1993, Diamond et al., 1997, Mavaddat et al., 1999). We argue that ACoA amnesia results from basal forebrain damage that disrupts learning in the hippocampal region (Myers et al., 2001, Myers et al., 2002). Cholinergic treatments are used to treat patients with ACoA aneurysm (Benke, Koylu, Delazer, Trinka, & Kemmler, 2005), which is consistent with a dysfunction to the cholinergic system in these patients. See Table 1 for summary of patient populations’ performance on the acquired equivalence task.

Our model seeks to explain how various brain disorders affect acquisition and transfer generalization performance by simulating the interactions between changes in dopamine and acetylcholine in the basal ganglia and hippocampal region, respectively, as well as from damage to either or both regions. The model integrates features from our existing models of the basal ganglia (Moustafa & Gluck, 2010) and hippocampal region (Moustafa et al., 2009, Myers et al., 1995). In addition, the model explains how disruption to the dopaminergic (as in Parkinson’s disease) or cholinergic (as in ACoA aneurysm) systems affects acquisition performance. Dopamine is produced in the midbrain and is projected to the basal ganglia and prefrontal cortex. Several studies show that phasic dopamine is important for stimulus–response learning (Schultz et al., 1997, Wickens et al., 1996). Our model assumes that phasic dopamine is key for stimulus–response learning through synaptic modification in the basal ganglia, as we have done in our past models of the basal ganglia (Guthrie et al., 2009, Moustafa and Gluck, 2010, Moustafa and Maida, 2007).

The basal forebrain is an important source of the neurotransmitter acetylcholine throughout the cortex, with the medial septum in particular sending acetylcholine to the hippocampal region (Hasselmo and Barkai, 1995, Nauta and Feirtag, 1986, Nolte, 1993). In a recent study, Kukolja, Thiel, and Fink (2009) found that human subjects taking cholinergic medications show enhanced hippocampal functions such as encoding. Septal lesions disrupt hippocampal function and impair acquisition of conditioned eyeblinking in rabbits (Berry and Thompson, 1979, Salvatierra and Berry, 1989, Powell et al., 1976). Similarly, studies show that scopolamine (an acetylcholine antagonist) impairs encoding of new information in humans and animals, a behavioral task that relies on the integrity of the hippocampal region (Carli et al., 1997, Mewaldt and Ghoneim, 1979). Furthermore, rodent studies have shown that acetylcholine is important for synaptic modification in the hippocampal region (Huerta & Lisman, 1993). In agreement with these experimental studies, our model assumes that acetylcholine plays a critical role in learning in the hippocampal region, much as in our earlier models of septo-hippocampal function in associative learning (Myers et al., 1996, Rokers et al., 2002).

Our integrated model of basal ganglia and hippocampal region function also attempts to explain how patients with ACoA aneurysm or hippocampal atrophy—brain disorders that affect the hippocampal region—show different performance in the acquired equivalence task. The model assumes that hippocampal atrophy (and also mild Alzheimer’s disease and hypoxia) impairs hippocampal function, while ACoA aneurysm slows down learning in the hippocampal region. The model also shows how patients with ACoA aneurysm or Parkinson’s disease—brain disorders that affect different brain systems—show similar performance in the acquired equivalence task. The model shows that decreasing learning rate parameter values either in the hippocampal region or basal ganglia modules slows down acquisition but does not affect transfer generalization performance. See Table 1 for summary of various patient groups’ performance in the acquired equivalence task.

The model has two modules: basal ganglia and hippocampal region (Fig. 1). In agreement with most models (Frank, 2005, Moustafa and Gluck, 2010), the basal ganglia is key for stimulus–response learning. Also in agreement with computational models and experimental data (Dusek and Eichenbaum, 1997, Gluck and Myers, 1993), we assume that the hippocampal region is important for stimulus–stimulus representational processes. In the model, dopamine is key for learning in the basal ganglia, while acetylcholine is key for learning in the hippocampal region (see Appendix A for more details on model simulations).