Greater Education Does Not Reduce the Rate of Brain Aging

Post by Lincoln Tracy

What's the science?

Educational attainment has been linked with numerous advantages across an individual’s lifespan. One proposed advantage of education relates to brain aging, where education either acts as a protector, or contributes to our cognitive reserve (how resilient our brain is). However, cross-sectional studies investigating the association between education and brain aging (where participants are only examined at one point in time) are inconclusive. In addition, data from longitudinal studies (where participants are examined at multiple time points, often months or years apart) on this association are sparse. This week in PNAS, Nyberg and colleagues used two large-scale, longitudinal datasets to test the association between education and brain aging. Brain aging was defined as brain atrophy measured by structural magnetic resonance imaging [MRI]).

How did they do it?

The authors obtained MRI and educational data from two large-scale, longitudinal studies: the European Lifebrain project and the UK Biobank. Specifically, they obtained data for 1844 MRI scans from 735 participants (29-91 years old, 368 females) from the Lifebrain project and 2578 MRI scans from 1289 participants (47-82 years old, 660 females) from the UK Biobank. Education was measured as the number of years spent in formal schooling for the Lifebrain project and whether participants had obtained a college or university degree in the UK Biobank sample. MRI data were processed to determine hippocampal, intracranial, and cortical volume. Associations between education and cortical volume in both datasets were then tested in cross-sectional and longitudinal analyses.  

What did they find?

Both the Lifebrain project and the UK Biobank found age-related reductions in hippocampal volume over time. There was no association between education and cortical or hippocampal volume over time when the two datasets were analyzed separately. However, cross-sectional analysis revealed associations between education and regional cortical volume around the left central sulcus.  

What's the impact?

Despite examining almost 4500 MRI scans from over 2000 individuals, the authors found no evidence to support the theory that greater amounts of education lead to decreased rates of brain aging. These findings, together with the existing literature, suggest that individuals with higher education develop more of a “passive” cognitive reserve compared to individuals with lower education, which is eroded as they age. In other words, brain aging occurs at the same rate regardless of how much education an individual has, but a greater level of education provides a greater reserve of brain (or proportion of the brain) that is required to age before adverse outcomes such as dementia occur.  

Nyberg et al. Educational attainment does not influence brain aging. PNAS (2021). Access the original scientific publication here.

Autophagic Degradation of the Dopamine Transporter Regulates Behavioural Effects of Cocaine

Post by Amanda McFarlan

What's the science?

Cocaine blocks dopamine reuptake and causes prolonged dopamine signaling in the brain by directly binding to the dopamine transporter. Researchers, however, have speculated that this might not be cocaine’s only mechanism of action, since other drugs that block dopamine reuptake, such as sibutramine or bupropion, fail to induce the stimulant effects of cocaine. Recent findings have shown that cocaine may be associated with autophagy, a lysosomal process that involves the degradation and recycling of cellular components to maintain cellular homeostasis. This week in Molecular Psychiatry, Harraz and colleagues examine the role of autophagy in regulating the molecular and behavioural effects of cocaine.

How did they do it?

The authors explored whether cocaine administration in cortical and ventral midbrain neuronal cultures induced autophagy. They used confocal microscopy and transmission electron microscopy to quantify levels of LC3-II, a microtubule-associated protein that tags the autophagosomal membranes. Then, the authors investigated the role of autophagy in the behavioural stimulant effects associated with cocaine. To do this, they treated mice with either one of three autophagy inhibitors (HCQ, vacuolin-1, or SBI-0206965) or saline 45 minutes prior to being placed in an open field test. After measuring baseline locomotor activity, they delivered intraperitoneal injections of either cocaine or saline and placed the mice back in the open field test to monitor locomotor behaviour. Next, the authors performed synaptosome fractions (separation of molecules in the synapse based on size or density) to explore the role of cocaine-induced autophagy on the degradation of the dopamine transporter. Finally, to examine the effect of autophagy on the rewarding actions of cocaine, the authors treated mice with either HCQ (an autophagy inhibitor) or saline prior to administering cocaine in the conditioned place preference paradigm.

What did they find?

The authors determined that cocaine induces autophagy with high potency in neurons. They showed that cocaine-induced locomotor stimulation was greatly reduced in mice that were treated with an autophagy inhibitor compared to mice that were treated with saline. Next, synaptosomal fractions from the nucleus accumbens (an area of the brain associated with reward) revealed that the dopamine transporter was largely depleted in mice that had been treated with cocaine compared to mice treated with saline. The cocaine-induced depletion of the dopamine transporter could be rescued with the administration of an autophagy inhibitor 90 minutes prior to cocaine administration. Notably, cocaine’s effects were selective for the dopamine transporter since levels of the serotonin transporter or tyrosine hydroxylase (an enzyme involved in the synthesis of dopamine) were unchanged. Finally, the authors found that cocaine-induced conditioned place preference was impaired in mice treated with HCQ compared to saline, suggesting that autophagy is involved in regulating the rewarding effects of cocaine.

What’s the impact?

This study is the first to show that cocaine induces autophagic degradation of the dopamine transporter with high potency. The authors found that this cocaine-induced autophagy was important for regulating behavioural characteristics associated with cocaine, including locomotion and reward. These findings provide new insights into the mechanisms by which cocaine acts in the brain.

Harraz et al. Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter. Molecular Psychiatry (2021). Access the original scientific publication here.

Deep Projection Neurons in the Prefrontal Cortex Enable Cognitive Flexibility via Feedback Monitoring

Post by Elisa Guma

What's the science?

Cognitive flexibility refers to our ability to adapt and update strategies in response to changing environmental stimuli and is impaired in individuals across a range of psychiatric disorders. A large body of evidence from both rodent and human studies suggests that the prefrontal cortex (PFC) plays a critical role in supporting this behaviour, however, the mechanisms underlying this role of the PFC in cognitive flexibility remain to be elucidated. The PFC is thought to provide an attentional filter for the brain that biases sensorimotor responses during set-shifting (task switching to focus on a new, relevant stimulus), however, an alternative hypothesis suggests that the PFC supports set-shifting by monitoring feedback in response to recent decisions. This week in Cell, Spellman and colleagues investigate whether the PFC supports set-shifting behaviour through feedback monitoring or through attentional modulation of sensorimotor responses in a series of experiments in mice.

How did they do it?

The authors trained adult male water-deprived mice on an attentional set-shifting task comprising a successive series of stimulus-response discriminations in which the relevant stimuli (signifying a reward) and irrelevant stimuli were changed. Briefly, mice were presented one of two possible whisker vibration stimuli, and one of two possible odor stimuli to which they had to respond by licking either a left or right lick port to receive a water reward. They had to learn that either a specific whisker or odor stimulus signaled the location of the reward and to ignore irrelevant stimuli. These associations changed throughout the task, requiring mice to unlearn the previous association and learn the new one. Trials were classified into congruent trials in which whisker and odor rules cued the same response direction, or incongruent trials, in which whisker and odor rules cued opposite directions.

While the mice performed this task, the authors used GcaMP6f-mediated two-photon calcium imaging to examine neural activity in the PFC, for all neurons, as well as for two specific projections hypothesized to be critical for this task: a projection to the ventromedial striatum (PFC-VMS), or a projection to the mediodorsal thalamus (PFC-MDT). Neural activity data were classified, using a machine learning model (a support vector machine-based decoder), into different categories including whisker stimulus (ex: 35 versus 210 Hz), odor stimulus (ex: almond versus olive oil), response (left/right), outcome (correct/incorrect), and rule (attend to whisker or odor). Based on these categories, the authors were able to investigate the specific within-trial timepoints at which neurons were encoding either response or outcome, and how these signals were carried over into subsequent trials.

In order to shed light on the circuitry underlying the PFC’s role in attentional set-shifting, the authors used optogenetics to selectively inhibit PFC activity either during the attentional set-shifting trials or during the intertrial period following either congruent or incongruent trials. In addition to assessing the role of the PFC-VMS and PFC-MDT pathways in supporting rule-guided response, they also investigated the role of the posterior parietal cortex based on previous research implicating this region in cognitive flexibility and monitoring sensory history. Finally, the authors examined whether the spatial distribution of PFC neurons played an important role. They used retrograde tracers to specifically target either deep or superficial projection neurons from the PFC to ACC.

What did they find?

The authors found that the temporal components associated with whisker and odor stimulus peaked during the stimulus presentation, as expected, while components associated with outcome peaked during the inter-trial interval and persisted for up to four trials. This suggests that the response-associated patterns lag, rather than lead, the animal’s behavioural choice.

The optogenetic manipulation of PFC activity during the attentional set-shifting task led to an impairment in performance only when activation was silenced during the intertrial interval following incongruent trials, but not congruent trials, and not during the stimulus presentation. This suggests that interference with prior trial feedback, rather than preparation for the subsequent trial, caused impairment in performance. Additionally, silencing the posterior parietal cortex neurons during trials impaired performance on the incongruent but not congruent trials, suggesting that the posterior parietal cortex mediates responding in the task in a specifically rule-dependent manner.

Contrary to expectations, the two populations of neurons from the PFC-VMS and PFC-MDT pathways showed a striking degree of overall similarity in their task responsiveness. Even though there was no distinction between these two pathways, there was a great degree of heterogeneity in the functional properties of the neurons studies, with a range of correct- or incorrect-preferring neurons, which they probed further. They found that the heterogeneity in neural response was attributed to the depth of the cortical layer, highlighting the importance of deep cortical projection to the anterior cingulate cortex.

What's the impact?

These findings provide a novel model for the role of the PFC in cognitive flexibility. Rather than mediating top-down cognitive control, the PFC was shown to integrate and maintain representations of recent behaviours and their consequences. Future work may seek to elucidate the potential role of certain neurotransmitter systems, such as acetylcholine, as it plays a key role in mediating feedback monitoring signals in the brain. Further, this work could aid in our understanding of how neural circuitry may be impaired in neurodevelopmental disorders exhibiting attentional set-shifting deficits but should include the use of female mice.

Spellman al., Prefrontal deep projection neurons enable cognitive flexibility via persistent feedback monitoring. Cell (2021). The original scientific publication here.