Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1–3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10–20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

Rationale The 5-choice serial reaction time task (5-CSRTT) is a widely used operant task for measuring attention and motor impulsivity in rodents. Training animals in this task requires an extensive period of daily operant sessions. Recently, a self-paced, automated version of this task has been developed for mice, which substantially reduces training time. Whether a similar approach is effective for rats is currently unknown. Objective Here, we tested whether attention and impulsivity can be assessed in rats with a self-paced version of the 5-CSRTT. Methods Operant boxes were connected to home-cages with tunnels. Two groups of rats self-paced their training by means of an automated script. The first group of animals was allowed unlimited access (UA) to start trials in the task; for the second group, trial availability was restricted to the first 2.5 h of the dark cycle (TR). Task parameter manipulations, such as variable inter-trial intervals and stimulus durations as well as pharmacological challenges with scopolamine, were tested to validate the task. Results Self-paced training took less than 1 week. Animals in the UA group showed higher levels of omissions compared with the TR group. In both protocols, variable inter-trial intervals increased impulsivity, and variable stimulus durations decreased attentional performance. Scopolamine affected cognitive performance in the TR group only. Conclusions Home-cage-based training of the 5-CSRTT in rats, especially the TR protocol, presents a valid and fast alternative for measuring attention and impulsivity.

The number of breast cancer survivors is gradually increasing and a subset of these patients experience long-term adverse effects of adjuvant systemic therapy, including cognitive decline. Surprisingly, relatively little is known about the long-term adverse effects of endocrine treatment on cognition. As 75% of all patients with breast cancer are eligible to receive hormonal treatment, understanding the potential neurocognitive adverse effects of such therapy is of utmost importance. Concerns about adverse cognitive effects of adjuvant endocrine therapy are timely, as recently updated guidelines recommend increasing the length of such therapy from 5 years to 10 years for a subset of patients. The decline of cognitive functions can have a detrimental impact on quality of life and might interfere with independent living. This Review discusses the tissue-selective side effects of endocrine therapies and specifically their impact on cognitive function, on the basis of clinical data; the neurobiological effects of endocrine therapies as observed in preclinical models are also discussed. We highlight the critical issues that need to be addressed in future preclinical and clinical studies in order to best assess the cognitive effects of endocrine treatment in patients with breast cancer.

Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.

SummaryNeocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. It has also not been addressed whether these neurons release both neurotransmitters acetylcholine (ACh) and GABA. Here, we find that in the medial prefrontal cortex (mPFC), ChAT-VIP neurons directly excite interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 by fast cholinergic transmission. Dual recordings of presynaptic ChAT-VIP neurons and postsynaptic L1 interneurons show fast nicotinic receptor currents strictly time-locked to single presynaptic action potentials. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons, but instead depolarized fast spiking and low threshold spiking interneurons. Finally, we find that ChAT-VIP neurons control attention behaviour distinctly from basal forebrain ACh inputs to mPFC. Our findings show that ChAT-VIP neurons are a local source of cortical ACh, that directly excite pyramidal and interneurons throughout cortical layers.

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The neuropeptide vasoactive intestinal peptide is expressed at high levels in a subset of neurons in ventral region of the suprachiasmatic nucleus (SCN). While VIP is known to be important for the synchronization of the SCN network, the role of VIP in photic regulation of the circadian system has received less attention. In the present study, we found that the light-evoked increase in electrical activity in vivo was unaltered by the loss of VIP. In the absence of VIP, the ventral SCN still exhibited NMDA-evoked responses in a brain slice preparation although the absolute levels of neural activity before and after treatment were significantly reduced. Next, we used calcium imaging techniques to determine if the loss of VIP altered the calcium influx due to retinohypothalamic tract stimulation. The magnitude of the evoked calcium influx was not reduced in the ventral SCN but did decline in the dorsal SCN regions. We examined the time course of the photic induction of Period1 in the SCN using in situ hybridization in VIP-mutant mice. We found that the initial induction of Period1 was not reduced by the loss of this signaling peptide. However, the sustained increase in Period1 expression (after 30 min) was significantly reduced. Similar results were found by measuring the light-induction of cFOS in the SCN. These findings suggest that VIP is critical for longer term changes within the SCN circuit but does not play a role in the acute light response.