Jeffrey C. Erlich

Distinct relationships of parietal and prefrontal cortices to evidence accumulation

Gradual accumulation of evidence is thought to be fundamental for decision-making, and its neural correlates have been found in several brain regions. Here we develop a generalizable method to measure tuning curves that specify the relationship between neural responses and mentally accumulated evidence, and apply it to distinguish the encoding of decision variables in posterior parietal cortex and prefrontal cortex (frontal orienting fields, FOF). We recorded the firing rates of neurons in posterior parietal cortex and FOF from rats performing a perceptual decision-making task. Classical analyses uncovered correlates of accumulating evidence, similar to previous observations in primates and also similar across the two regions. However, tuning curve assays revealed that while the posterior parietal cortex encodes a graded value of the accumulating evidence, the FOF has a more categorical encoding that indicates, throughout the trial, the decision provisionally favoured by the evidence accumulated so far. Contrary to current views, this suggests that premotor activity in the frontal cortex does not have a role in the accumulation process, but instead has a more categorical function, such as transforming accumulated evidence into a discrete choice. To probe causally the role of FOF activity, we optogenetically silenced it during different time points of the trial. Consistent with a role in committing to a categorical choice at the end of the evidence accumulation process, but not consistent with a role during the accumulation itself, a behavioural effect was observed only when FOF silencing occurred at the end of the perceptual stimulus. Our results place important constraints on the circuit logic of brain regions involved in decision-making.

Phospholipid-metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity.

Abstract: Damage to brain membrane phospholipids may play an important role in the pathogenesis of Alzheimers disease (AD); however, the critical metabolic processes responsible for the generation and repair of membrane phospholipids affected by the disease are unknown. We measured the activity of key phospholipid catabolic and anabolic enzymes in morphologically affected and spared areas of autopsied brain of patients with AD and in matched control subjects. The activity of the major catabolic enzyme phospholipase A2 (PLA2), measured in both the presence and absence of Ca2+, was significantly decreased (−35 to −53%) in parietal and temporal cortices of patients with AD. In contrast, the activities of lysophospholipid acyltransferase, which recycles lysophospholipids into intact phospholipids, and glycerophosphocholine phosphodiesterase, which returns phospholipid catabolites to be used in phospholipid resynthesis, were increased by ∼50–70% in the same brain areas. Brain activities of enzymes involved in de novo phospholipid synthesis (ethanolamine kinase, choline kinase, choline phosphotransferase, phosphoethanolamine cytidylyltransferase, and phosphocholine cytidylyltransferase) were either normal or only slightly altered. The activities of PLA2 and acyltransferase were normal in the degenerating cerebellum of patients with spinocerebellar atrophy type 1, whereas the activity of glycerophosphocholine phosphodiesterase was reduced, suggesting that the alterations in AD brain were not nonspecific consequences of neurodegeneration. Our data suggest that compensatory phospholipid metabolic changes are present in AD brain that reduce the rate of phospholipid loss via both decreased catabolism (PLA2) and increased phospholipid resynthesis (acyltransferase and glycerophosphocholine phosphodiesterase).

Distinct effects of prefrontal and parietal cortex inactivations on an accumulation of evidence task in the rat

Numerous brain regions have been shown to have neural correlates of gradually accumulating evidence for decision-making, but the causal roles of these regions in decisions driven by accumulation of evidence have yet to be determined. Here, in rats performing an auditory evidence accumulation task, we inactivated the frontal orienting fields (FOF) and posterior parietal cortex (PPC), two rat cortical regions that have neural correlates of accumulating evidence and that have been proposed as central to decision-making. We used a detailed model of the decision process to analyze the effect of inactivations. Inactivation of the FOF induced substantial performance impairments that were quantitatively best described as an impairment in the output pathway of an evidence accumulator with a long integration time constant (>240 ms). In contrast, we found a minimal role for PPC in decisions guided by accumulating auditory evidence, even while finding a strong role for PPC in internally-guided decisions. DOI: http://dx.doi.org/10.7554/eLife.05457.001

Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra : Possible implications for Parkinson's disease

To determine whether increased oxidative stress in substantia nigra of patients with idiopathic Parkinsons disease might be related to decreased ability of nigral cells to detoxify oxidized membrane phospholipids, we compared levels of the major phospholipid metabolizing enzymes in autopsied substantia nigra with those in non-nigral (n = 11) brain areas of the normal human brain. Whereas most enzymes possessed a relatively homogeneous distribution, the activity of the major phospholipid catabolizing enzyme phospholipase A2, assayed in the presence of calcium ions, varied amongst different regions, with substantia nigra possessing the lowest activity. Similarly, calcium-independent phospholipase A2 activity, although possessing a relatively homogeneous regional distribution, was also low in the substantia nigra. This, coupled with low activity of phosphoethanolamine- and phosphocholine-cytidylyltransferases, major regulatory enzymes of phospholipid synthesis, in this brain region, suggest that the rate of phospholipid turnover is low in the substantia nigra. Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra might result in reduced ability to repair oxidative membrane damage, as may occur in Parkinsons disease.

Cortical and Subcortical Contributions to Short-Term Memory for Orienting Movements.

Neural activity in frontal cortical areas has been causally linked to short-term memory (STM), but whether this activity is necessary for forming, maintaining, or reading out STM remains unclear. In rats performing a memory-guided orienting task, the frontal orienting fields in cortex (FOF) are considered critical for STM maintenance, and during each trial display a monotonically increasing neural encoding for STM. Here, we transiently inactivated either the FOF or the superior colliculus and found that the resulting impairments in memory-guided orienting performance followed a monotonically decreasing time course, surprisingly opposite to the neural encoding. A dynamical attractor model in which STM relies equally on cortical and subcortical regions reconciled the encoding and inactivation data. We confirmed key predictions of the model, including a time-dependent relationship between trial difficulty and perturbability, and substantial, supralinear, impairment following simultaneous inactivation of the FOF and superior colliculus during memory maintenance.

The role of the lateral amygdala in the retrieval and maintenance of fear-memories formed by repeated probabilistic reinforcement.

The lateral nucleus of the amygdala (LA) is a key element in the neural circuit subserving Pavlovian fear-conditioning, an animal model of fear and anxiety. Most studies have focused on the role of the LA in fear acquisition and extinction, i.e., how neural plasticity results from changing contingencies between a neutral conditioned stimulus (CS) (e.g., a tone) and an aversive unconditioned stimulus (US) (e.g., a shock). However, outside of the lab, fear-memories are often the result of repeated and unpredictable experiences. Examples include domestic violence, child abuse or combat. To better understand the role of the LA in the expression of fear resulting from repeated and uncertain reinforcement, rats experienced a 30% partial reinforcement (PR) fear-conditioning schedule four days a week for four weeks. Rats reached asymptotic levels of conditioned-fear expression after the first week. We then manipulated LA activity with drug (or vehicle) (VEH) infusions once a week, for the next three weeks, before the training session. LA infusions of muscimol (MUSC), a GABA-A agonist that inhibits neural activity, reduced CS evoked fear-behavior to pre-conditioning levels. LA infusions of pentagastrin (PENT), a cholecystokinin-2 (CCK) agonist that increases neural excitability, resulted in CS-evoked fear-behavior that continued past the offset of the CS. This suggests that neural activity in the LA is required for the retrieval of fear memories that stem from repeated and uncertain reinforcement, and that CCK signaling in the LA plays a role in the recovery from fear after the removal of the fear-evoking stimulus.

Minimal impairment in a rat model of duration discrimination following excitotoxic lesions of primary auditory and prefrontal cortices.

We present a behavioral paradigm for the study of duration perception in the rat, and report the result of neurotoxic lesions that have the goal of identifying sites that mediate duration perception. Using a two-alternative forced-choice paradigm, rats were either trained to discriminate durations of pure tones (range = [200,500] ms; boundary = 316 ms; Weber fraction after training = 0.24 ± 0.04), or were trained to discriminate frequencies of pure tones (range = [8,16] kHz; boundary = 11.3 kHz; Weber = 0.16 ± 0.11); the latter task is a control for non-timing-specific aspects of the former. Both groups discriminate the same class of sensory stimuli, use the same motions to indicate decisions, have identical trial structures, and are trained to psychophysical threshold; the tasks are thus matched in a number of sensorimotor and cognitive demands. We made neurotoxic lesions of candidate timing-perception areas in the cerebral cortex of both groups. Following extensive bilateral lesions of the auditory cortex, the performance of the frequency discrimination group was significantly more impaired than that of the duration discrimination group. We also found that extensive bilateral lesions of the medial prefrontal cortex resulted in little to no impairment of both groups. The behavioral framework presented here provides an audition-based approach to study the neural mechanisms of time estimation and memory for durations.

Decision-making behaviors: weighing ethology, complexity, and sensorimotor compatibility.

Rodent decision-making research aims to uncover the neural circuitry underlying the ability to evaluate alternatives and select appropriate actions. Designing behavioral paradigms that provide a solid foundation to ask questions about decision-making computations and mechanisms is a difficult and often underestimated challenge. Here, we propose three dimensions on which we can consider rodent decision-making tasks: ethological validity, task complexity, and stimulus-response compatibility. We review recent research through this lens, and provide practical guidance for researchers in the decision-making field.

Rat Prefrontal Cortex Inactivations during Decision Making Are Explained by Bistable Attractor Dynamics

Two-node attractor networks are flexible models for neural activity during decision making. Depending on the network configuration, these networks can model distinct aspects of decisions including evidence integration, evidence categorization, and decision memory. Here, we use attractor networks to model recent causal perturbations of the frontal orienting fields (FOF) in rat cortex during a perceptual decision-making task (Erlich, Brunton, Duan, Hanks, & Brody, 2015). We focus on a striking feature of the perturbation results. Pharmacological silencing of the FOF resulted in a stimulus-independent bias. We fit several models to test whether integration, categorization, or decision memory could account for this bias and found that only the memory configuration successfully accounts for it. This memory model naturally accounts for optogenetic perturbations of FOF in the same task and correctly predicts a memory-duration-dependent deficit caused by silencing FOF in a different task. Our results provide mechanistic support for a “postcategorization” memory role of the FOF in upcoming choices.

Neuroscience: What to do and how

Decisions can differ depending on the context that surrounds them. Analyses of the prefrontal cortex region of the monkey brain indicate that a dynamical process at the neuronal population level controls this behaviour. See Article p.78 The neurons of the primate prefrontal cortex represent multiple aspects of sensory stimuli and have task-dependent, time-varying responses. How these complex responses represent relevant aspects of their inputs or contribute to behaviour in different contexts remains unclear. Valerio Mante et al. show here that when monkeys perform a context-dependent sensorimotor task, task-relevant and task-irrelevant signals are intermingled in single units of the prefrontal cortex, but are readily understood in the framework of a dynamical process unfolding at the level of the population. A recurrently connected neural network model reproduces key features of the data and suggests a novel mechanism for selection and integration of task-relevant evidence towards a decision.