In real-world decision-making scenarios, negative consequences do not always occur immediately after a choice. This delay between action and outcome drives the underestimation, or “delay discounting”, of punishment. While the neural substrates underlying sensitivity to immediate punishment have been well-studied, there has been minimal investigation of delayed consequences. Here, we assessed the role of lateral orbitofrontal cortex (LOFC) and basolateral amygdala (BLA), two regions implicated in cost/benefit decision-making, in sensitivity to delayed vs immediate punishment. The delayed punishment decision-making task (DPDT) was used to measure delay discounting of punishment in rodents. During DPDT, rats choose between a small, single pellet reward and a large, three pellet reward accompanied by a mild foot shock. As the task progresses, the shock is preceded by a delay that systematically increases or decreases throughout the session. We observed that rats avoid choices associated with immediate punishme...

Opsin-3 ( Opn3 , encephalopsin) was the first nonvisual opsin gene discovered in mammals. Since then, several Opn3 functions have been described, and in two cases (adipose tissue, smooth muscle) light sensing activity is implicated. In addition to peripheral tissues, Opn3 is robustly expressed within the central nervous system, for which it derives its name. Despite this expression, no studies have investigated developmental or adult CNS consequences of Opn3 loss-of-function. Here, the behavioral consequences of mice deficient in Opn3 were investigated. Opn3 -deficient mice perform comparably to wild-type mice in measures of motor coordination, socialization, anxiety-like behavior, and various aspects of learning and memory. However, Opn3 -deficient mice have an attenuated acoustic startle reflex (ASR) relative to littermates. This deficit is not because of changes in hearing sensitivity, although Opn3 was shown to be expressed in auditory and vestibular structures, including cochlear outer hair cells. Int...

Habituation is a conserved adaptive process essential for incoming information assessment, which drives behavioral response decrement to recurrent inconsequential stimuli and does not involve sensory adaptation, or fatigue. Although the molecular mechanisms underlying the process are not well understood, habituation has been reported defective in a number of disorders including schizophrenia. We demonstrate that loss of furin1 , the Drosophila homolog of a gene whose transcriptional downregulation has been linked to schizophrenia, results in defective habituation to recurrent footshocks in mixed sex populations. The deficit is reversible by transgenic expression of the Drosophila or human Furin in adult α,/β, mushroom body neurons and by acute oral delivery of the typical antipsychotic Haloperidol and the atypical Clozapine, which are commonly used to treat schizophrenic patients. The results validate the proposed contribution of Furin downregulation in schizophrenia and suggest that defective footshock ha...

Distinct computations are performed at multiple brain regions during the encoding of spatial environments. Neural representations in the hippocampal, entorhinal and head direction (HD) networks during spatial navigation have been clearly documented, while the representational properties of the Subicular Complex (SC) are relatively under-explored, even though it has extensive anatomical connections with various brain regions involved in spatial information processing. We simultaneously recorded single units from different sub-regions of the SC in male rats while they ran clockwise on a centrally placed textured circular track (four different textures, each covering a quadrant), surrounded by six distal cues. The neural activity was monitored in standard sessions by maintaining the same configuration between the cues, while in cue manipulation sessions, the distal and local cues were either rotated in opposite directions to create a mismatch between them, or the distal cues were removed. We report a highly c...

There is currently no robust method to evaluate how built environment design affects our emotion. Understanding emotion is significant, as it influences cognitive processes, behaviour, and wellbeing, and is linked to the functioning of physiological systems. As mental health problems are becoming more prevalent, and exposure to indoor environments is increasing, it is important we develop rigorous methods to understand whether design elements in our environment affect emotion. This study examines whether the scale of interior built environments modulate neural networks involved in emotion regulation. Using a cave automatic virtual environment and controlling for indoor environmental quality, 66 adults (31 female, aged 18-55) were exposed to context-neutral enclosed indoor room scenes to understand whether built environment scale affected self-report, autonomic nervous system, and central nervous system correlates of emotion. Our results revealed enlarged scale increased electroencephalography (EEG) power i...

Anterolateral system (AS) neurons transmit pain signals from the spinal cord to the brain. Their morphology, anatomy and physiological properties have been extensively characterised and suggest that specific AS neurons and their brain targets are concerned with the discriminatory aspects of noxious stimuli, such as their location or intensity, and their motivational/emotive dimension. Among the recently unravelled molecular markers of AS neurons is the developmentally-expressed transcription factor Phox2a, affording us the opportunity to selectively disrupt the embryonic wiring of AS neurons to gain insights into the logic of their adult function. Since mice with a spinal cord-specific loss of the netrin-1 receptor DCC have increased AS neuron innervation of ipsilateral brain targets and defective noxious stimulus localisation or topognosis, we generated mice of either sex carrying a deletion of Dcc in Phox2a neurons. Such DccPhox2a mice displayed impaired topognosis along the rostrocaudal axis, but with l...

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high-affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rs in vitro . Nicotine, with lower pKa and α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labelled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4β2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4β2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals we...

In times of stress or danger, the autonomic nervous system (ANS) signals the fight or flight response. A canonical function of ANS activity is to globally mobilize metabolic resources, preparing the organism to respond to threat. Yet a body of research has demonstrated that, rather than displaying a homogenous pattern across the body, autonomic responses to arousing events — as measured through changes in electrodermal activity (EDA) — can differ between right and left body locations. Surprisingly, an attempt to identify a function of ANS asymmetry consistent with its metabolic role has not been investigated. In the current study, we investigated whether asymmetric autonomic responses could be induced through limb-specific aversive stimulation. Participants were given mild electric stimulation to either the left or right arm while EDA was monitored bilaterally. In a group-level analyses, an ipsilateral EDA response bias was observed, with increased EDA response in the hand adjacent to the stimulation. This...

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that recurring cholinergic activation of α7 nACh receptors expressed in oriens-lacunosum-moleculare (OLMα2) interneurons can directly induce LTP in Schaffer collateral (SC)–CA1 synapses. Here, we pair in vitro studies with biophysically based modeling to uncover the underlying mechanisms. According to our model, α7 nAChR activation increases OLM GABAergic activity. This results in the inhibition of the fast-spiking interneurons that provide feedforward inhibition onto CA1 pyramidal neurons. This disinhibition, paired with tightly timed SC stimulation, can induce potentiation at the excitatory synapses of CA1 pyramidal neurons. Our work details the role of cholinergic modulation in disinhibition-induced hippocampal plasticity. It relates the timing of ch...

To understand language, we must infer structured meanings from real-time auditory or visual signals. Researchers have long focused on word-by-word structure building in working memory as a mechanism that might enable this feat. However, some have argued that language processing does not typically involve rich word-by-word structure building, and/or that apparent working memory effects are underlyingly driven by surprisal (how predictable a word is in context). Consistent with this alternative, some recent behavioral studies of naturalistic language processing that control for surprisal have not shown clear working memory effects. In this fMRI study, we investigate a range of theory-driven predictors of word-by-word working memory demand during naturalistic language comprehension in humans of both sexes under rigorous surprisal controls. In addition, we address a related debate about whether the working memory mechanisms involved in language comprehension are language-specialized or domain-general. To do so...