Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice.

Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.

Chemotherapeutic drug elemene induces pain and anxiety-like behaviors by activating GABAergic neurons in the lateral septum of mice.

Most chemotherapeutic drugs are potent and have a very narrow range of dose safety and efficacy, most of which can cause many side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and serious side effect of chemotherapy for cancer treatment. However, its mechanism of action is yet to be fully elucidated. In the present study, we found that the treatment of the chemotherapy drug elemene induced hyperalgesia accompanied by anxiety-like emotions in mice based on several pain behavioral assays, such as mechanical allodynia and thermal hyperalgesia tests. Second, immunostaining for c-fos (a marker of activated neurons) further showed that elemene treatment activated several brain regions, including the lateral septum (LS), cingulate cortex (ACC), paraventricular nucleus of the thalamus (PVT), and dorsomedial hypothalamic nucleus (DMH), most notably in the GABAergic neurons of the lateral septum (LS). Finally, we found that both chemogenetic inhibition and apoptosis of LS neurons significantly reduced pain- and anxiety-like behaviors in mice treated with elemene. Taken together, these findings suggest that LS is involved in the regulation of elemene-induced chemotherapy pain and anxiety-like behaviors, providing a new target for the treatment of chemotherapy pain induced by elemene.

Orexin improves chronic restraint stress induced depressive-like behavior via modulating the lateral septum in mice.

The orexin system participates in the regulation of depression; however, its effects show significant heterogeneity, indicating the involvement of complex downstream neural circuit mechanisms. The lateral septum (LS), located downstream of the orexin system, contributes to depression. However, the effects and mechanisms underlying the orexin-mediated modulation of the LS in patients with depression remain unclear. Herein, we applied fiber photometry, chemogenetics, neuropharmacology, and in vitro electrophysiology to show that LS orexinergic afferents are sensitive to acute restraint and that chronic restraint stress (CRS) inhibits LS-projecting orexin neurons. Chemogenetic activation of LS orexinergic afferents or injection of orexin-A into the LS improved CRS-induced depression-like behavior. In vitro perfusion of orexin-A increased the action potential of somatostatin neurons in the LS. Overall, this study provides evidence that orexin improves depressive-like behavior by modulating the LS, and that this effect is probably mediated by the upregulation of LS somatostatin neurons.

The Roots of Science, Technology, Engineering, and Mathematics: What Are the Evolutionary and Neural Bases of Human Mathematics and Technology?

INTRODUCTION: Neural exaptations represent descent via transitions to novel neural functions. A primary transition in human cognitive and neural evolution was from a predominantly socially oriented primate brain to a brain that also instantiates and subserves science, technology, and engineering, all of which depend on mathematics. Upon what neural substrates and upon what evolved cognitive mechanisms did human capacities for science, technology, engineering, and mathematics (STEM), and especially its mathematical underpinnings, emerge? Previous theory focuses on roles for tools, language, and arithmetic in the cognitive origins of STEM, but none of these factors appears sufficient to support the transition. METHODS: In this article, I describe and evaluate a novel hypothesis for the neural origins and substrates of STEM-based cognition: that they are based in human kinship systems and human maximizing of inclusive fitness. RESULTS: The main evidence for this hypothesis is threefold. First, as demonstrated by anthropologists, human kinship systems exhibit complex mathematical and geometrical structures that function under sets of explicit rules, and such systems and rules pervade and organize all human cultures. Second, human kinship underlies the core algebraic mechanism of evolution, maximization of inclusive fitness, quantified as personal reproduction plus the sum of all effects on reproduction of others, each multiplied by their coefficient of relatedness to self. This is the only "natural" equation expected to be represented in the human brain. Third, functional imaging studies show that kinship-related cognition activates frontal-parietal regions that are also activated in STEM-related tasks. In turn, the decision-making that integrates kinship levels with costs and benefits from alternative behaviors has recently been shown to recruit the lateral septum, a hub region that combines internal (from the prefrontal cortex, amygdala, and other regions) and external information relevant to social behavior, using a dedicated subsystem of neurons specific to kinship. CONCLUSIONS: Taken together, these lines of evidence suggest that kinship systems and kin-associated behaviors may represent exaptations for the origin of human STEM.

Aberrant Phase Precession of Lateral Septal Cells in a Maternal Immune Activation Model of Schizophrenia Risk May Disrupt the Integration of Location with Reward.

Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential as an animal moves along a track toward a reward (phase precession). Whereas shallow precession slopes were observed in control group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the control group cells revealed that the population tended to converge toward a common firing phase as the animal approached the reward location. This suggested that phase coding in these cells might signal both reward location and the distance to reward. By comparison, the degree of phase convergence in the MIA-group cells was weak, and the region of peak convergence was distal to the reward location. These findings suggest that a schizophrenia risk factor disrupts the phase-based encoding of location-reward relationships in the LS, potentially smearing reward representations across space.SIGNIFICANCE STATEMENT It is unclear how spatial or contextual information generated by hippocampal cells is converted to a code that can be used to signal reward location in regions, such as the VTA. Here we provide evidence that the firing phase of cells in the lateral septum, a region that links the two areas, may code reward location in the firing phase of cells. This phase coding is disrupted in a maternal immune activation model of schizophrenia risk such that representations of reward may be smeared across space in maternal immune activation animals. This could potentially underlie erroneous reward processing and misattribution of salience in schizophrenia.

Transcriptomic analysis of paternal behaviors in prairie voles.

BACKGROUND: The importance of fathers' engagement in care and its critical role in the offspring's cognitive and emotional development is now well established. Yet, little is known on the underlying neurobiology due to the lack of appropriate animal models. In the socially monogamous and bi-parental prairie vole (Microtus ochrogaster), while 60-80% of virgin males show spontaneous paternal behaviors (Paternal), others display pup-directed aggression (Attackers). Here we took advantage of this phenotypic dichotomy and used RNA-sequencing in three important brain areas to characterize gene expression associated with paternal behaviors of Paternal males and compare it to experienced Fathers and Mothers. RESULTS: While Paternal males displayed the same range and extent of paternal behaviors as experienced Fathers, we observed structure-specific transcriptomic differences between parental behaviors phenotypes. Using differential expression, gene set expression, as well as co-expression network analyses, we found that phenotypic differences between Paternal males and Attackers were mainly reflected by the lateral septum (LS), and to a lower extent, the nucleus accumbens (NAc), transcriptomes. In the medial preoptic area (MPOA), the profiles of gene expression mainly reflected differences between females and males regardless of their parental behaviors phenotype. Functional enrichment analyses of those gene sets associated with Paternal males or Attackers in the LS and the NAc revealed the involvement of processes related to the mitochondria, RNA translation, protein degradation processes, as well as epigenetic regulation of gene expression. CONCLUSIONS: By leveraging the natural phenotypic differences in parental behaviors in virgin male prairie voles alongside fathers and mothers, we identified a marked structure- and phenotype-specific pattern of gene expression associated with spontaneous paternal behaviors independently from fatherhood and pair-bonding. The LS transcriptome related to the mitochondria, RNA translation, and protein degradation processes was thus highlighted as a primary candidate associated with the spontaneous display of paternal behaviors. Altogether, our observations further characterize the behavioral and transcriptomic signature of parental behaviors in the socially monogamous prairie vole and lay the groundwork to further our understanding of the molecular underpinnings of paternal behavior.

Long-term depression of excitatory transmission in the lateral septum.

Neurons in the lateral septum (LS) integrate glutamatergic synaptic inputs, primarily from hippocampus, and send inhibitory projections to brain regions involved in reward and the generation of motivated behavior. Motivated learning and drugs of abuse have been shown to induce long-term changes in the strength of glutamatergic synapses in the LS, but the cellular mechanisms underlying long-term synaptic modification in the LS are poorly understood. Here, we examined synaptic transmission and long-term depression (LTD) in brain slices prepared from male and female C57BL/6 mice. No sex differences were observed in whole cell patch-clamp recordings of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)- and N-methyl-d-aspartate receptor (NMDA-R)-mediated currents. Low-frequency stimulation of the fimbria fiber bundle (1 Hz 15 min) induced LTD of the LS field excitatory postsynaptic potential (fEPSP). Induction of LTD was blocked by the NMDA-R antagonist (d)-2-amino-5-phosphonovaleric acid (APV), but not the selective antagonist of GluN2B-containing NMDA-Rs ifenprodil. These results demonstrate the NMDA-R dependence of LTD in the LS. The LS is a sexually dimorphic structure, and sex differences in glutamatergic transmission have been reported in vivo; our results suggest sex differences observed in vivo result from network activity rather than intrinsic differences in glutamatergic transmission.NEW & NOTEWORTHY The lateral septum (LS) integrates information from hippocampus and other regions to provide context-dependent (top down or higher order) regulation of mood and motivated behavior. Learning and drugs of abuse induce long-term changes in the strength of glutamatergic projections to the LS; however, the cellular mechanisms underlying such changes are poorly understood. Here, we demonstrate there are no apparent sex differences in fast excitatory transmission and that long-term synaptic depression in the LS is NMDA-R dependent.

Activation of ventral CA1 hippocampal neurons projecting to the lateral septum during feeding.

A number of studies have reported the involvement of the ventral hippocampus (vHip) and the lateral septum (LS) in negative emotional responses. Besides these well-documented functions, they are also thought to control feeding behavior. In particular, optogenetic and pharmacogenetic interventions to LS-projecting vHip neurons have demonstrated that the vHip→LS neural circuit exerts an inhibition on feeding behavior. However, there have been no reports of vHip neuronal activity during feeding. Here, we focused on LS-projecting vCA1 neurons (vCA1→LS ) and monitored their activity during feeding behaviors in mice. vCA1→LS neurons were retrogradely labeled with adeno-associated virus carrying a ratiometric Ca2+ indicator and measured compound Ca2+ dynamics by fiber photometry. We first examined vCA1→LS activity in random food-exploring behavior and found that vCA1→LS activation seemed to coincide with food intake; however, our ability to visually confirm this during freely moving behaviors was not sufficiently reliable. We next examined vCA1→LS activity in a goal-directed, food-seeking lever-press task which temporally divided the mouse state into preparatory, effort, and consummatory phases. We observed vCA1→LS activation in the postprandial period during the consummatory phase. Such timing- and pathway-specific activation was not observed from pan-vCA1 neurons. In contrast, reward omission eliminated this activity, indicating that vCA1→LS activation is contingent on the food reward. Sated mice pressed the lever significantly fewer times but still ate food; however, vCA1→LS neurons were not activated, suggesting that vCA1→LS neurons did not respond to habitual behavior. Combined, these results suggest that gastrointestinal interoception rather than food-intake motions or external sensations are likely to coincide with vCA1→LS activity. Accordingly, we propose that vCA1→LS neurons discriminate between matched or unmatched predictive bodily states in which incoming food will satisfy an appetite. We also demonstrate that vCA1→LS neurons are activated in aversive/anxious situations in an elevated plus maze and tail suspension test. Future behavioral tests utilizing anxious conflict and food intake may reconcile the multiple functions of vCA1→LS neurons.

Vasopressin in the lateral septum decreases conditioned place preference to amphetamine and nucleus accumbens dopamine release.

The lateral septum (LS) is a limbic nucleus interconnected with several brain areas involved in the regulation of mood and reward. Vasopressin (AVP) is a neuropeptide that has been related to the effects of drugs of abuse, but its role in the addictive process is poorly understood. LS expresses a high density of AVP 1A receptors (V1A ). The aim of this work was to examine whether the modulation of LS AVP system affects the behavioral and neurochemical responses to amphetamine (AMPH) in male rats. Our results show that AMPH-induced conditioned place preference (CPP) produces a decrease in LS AVP content. Besides, we demonstrate that the microinjection of AVP in the LS impairs the expression of AMPH-induced CPP and that this effect is mediated by the activation of the V1A receptor in the LS. AVP microinjection in the LS elicited a decrease in neuronal activity in the nucleus accumbens (NAc) in animals subjected to AMPH conditioning. Finally, AVP microinjection in the LS decreased dopamine (DA) release in the NAc. Overall, our data demonstrate that intra-LS AVP diminishes the expression of AMPH conditioning behavior while decreasing neuronal activity and DA release in the NAc. Presumably, the effects of AVP in the LS produce an inhibition of GABAergic projections to the VTA, increasing local inhibitory tone in this nucleus, which in turn reduces the activity of DA projections to NAc. Thus, these results contribute to the knowledge about the role of AVP in LS in regulating the reward circuit and addictive like behaviors.

TMEM16B Calcium-Activated Chloride Channels Regulate Action Potential Firing in Lateral Septum and Aggression in Male Mice.

The lateral septum (LS) plays an important role in regulating aggression. It is well recognized that LS lesions lead to a dramatic increase in aggressive behaviors. A better understanding of LS neurophysiology and its functional output is therefore important to assess LS involvement in regulating aggression. The LS is a heterogeneous structure that maintains inputs and outputs with multiple brain regions, and is also divided into subregions that innervate one another. Thus, it is challenging to identify the exact cell type and projections for characterization. In this study, we determined the expression pattern of the calcium-activated chloride channel, TMEM16B, in the LS of both male and female mice. We then investigated the physiological contribution of the calcium-activated chloride channel to LS neuronal signaling. By performing whole-cell patch-clamp recording, we showed that TMEM16B alters neurotransmitter release at the hippocampal-LS synapse, and regulates spike frequency and spike frequency adaptation in subpopulations of LS neurons. We further demonstrated that loss of TMEM16B function promotes lengthened displays of aggressive behaviors by male mice during the resident intruder paradigm. In conclusion, our findings suggest that TMEM16B function contributes to neuronal excitability in subpopulations of LS neurons and the regulation of aggression in male mice.SIGNIFICANCE STATEMENT Aggression is a behavior that arose evolutionarily from the necessity to compete for limited resources and survival. One particular brain region involved in aggression is the lateral septum (LS). In this study, we characterized the expression of the TMEM16B calcium-activated chloride channel in the LS and showed that TMEM16B regulates the action potential firing frequency of LS neurons. We discovered that loss of TMEM16B function lengthens the displays of aggressive behaviors in male mice. These findings suggest that TMEM16B plays an important role in regulating LS neuronal excitability and behaviors associated with LS function, thereby contributing to our understanding of how the LS may regulate aggression.

Lateral septum inhibition reduces motivation for cocaine: Reversal by diazepam.

The lateral septum (LS) is a brain region implicated in motivation, addiction, anxiety, and affect. We recently found that LS is necessary for cocaine-seeking behaviors including conditioned place preference and reinstatement of extinguished drug seeking, which involve LS input to limbic regions including ventral tegmental area (VTA) and orexin neurons in hypothalamus. Here, we microinjected baclofen-muscimol (B-M) in LS prior to testing in a behavioral economics (BE) paradigm. We found that intra-LS B-M decreased motivation (increased demand elasticity; α) for cocaine, but did not change consumption at low effort (Q0 ). We also compared the effects of LS inhibition with the effects of treatment with the benzodiazepine diazepam, which has been shown to facilitate reward pathways and disinhibit VTA dopamine neurons. Pretreatment with diazepam blocked the effects of LS inhibition and restored cocaine demand to that following vehicle treatment. These changes in cocaine demand after LS inhibition or diazepam were not due to effects on anxiety, as both manipulations produced similar effects on anxiety measures but opposing effects on drug taking. Collectively, these studies point to LS as a critical region driving motivation for cocaine, likely through its interactions with the mesolimbic dopamine system.

Survival of a Novel Subset of Midbrain Dopaminergic Neurons Projecting to the Lateral Septum Is Dependent on NeuroD Proteins.

Midbrain dopaminergic neurons are highly heterogeneous. They differ in their connectivity and firing patterns and, therefore, in their functional properties. The molecular underpinnings of this heterogeneity are largely unknown, and there is a paucity of markers that distinguish these functional subsets. In this paper, we report the identification and characterization of a novel subset of midbrain dopaminergic neurons located in the ventral tegmental area that expresses the basic helix-loop-helix transcription factor, Neurogenic Differentiation Factor-6 (NEUROD6). Retrograde fluorogold tracing experiments demonstrate that Neurod6+ midbrain dopaminergic neurons neurons project to two distinct septal regions: the dorsal and intermediate region of the lateral septum. Loss-of-function studies in mice demonstrate that Neurod6 and the closely related family member Neurod1 are both specifically required for the survival of this lateral-septum projecting neuronal subset during development. Our findings underscore the complex organization of midbrain dopaminergic neurons and provide an entry point for future studies of the functions of the Neurod6+ subset of midbrain dopaminergic neurons.SIGNIFICANCE STATEMENT Midbrain dopaminergic neurons regulate diverse brain functions, including voluntary movement and cognitive and emotive behaviors. These neurons are heterogeneous, and distinct subsets are thought to regulate different behaviors. However, we currently lack the means to identify and modify gene function in specific subsets of midbrain dopaminergic neurons. In this study, we identify the transcription factor NEUROD6 as a specific marker for a novel subset of midbrain dopaminergic neurons in the ventral midbrain that project to the lateral septum, and we reveal essential roles for Neurod1 and Neurod6 in the survival of these neurons during development. Our findings highlight the molecular and anatomical heterogeneity of midbrain dopaminergic neurons and contribute to a better understanding of this functionally complex group of neurons.

Differential and complementary roles of medial and lateral septum in the orchestration of limbic oscillations and signal integration.

Anatomical differences between the medial and lateral septum have associated these nuclei with dissimilar functional roles and behaviours. While the medial septum has been implicated, predominantly, in theta rhythm generation along the septo-hippocampal axis, the lateral septum has mainly been investigated in the context of septo-hypothalamic dialogue. Recent advances suggest that medial and lateral septum are more closely functionally related than previously appreciated. Here, we explore the hypothesis that the medial septum mediates ascending septo-hippocampal theta propagation, while the lateral septum processes a descending hippocampo-septal and septo-hypothalamic reinforcement signal that mediates navigation during motivated behaviour. The generation and propagation of theta rhythm are critical for the initiation of exploratory behaviour. Indeed, theta signal processing of medial and lateral septum nuclei may well be involved in the integration of spatial, rewarding and locomotor signals across different brain networks. We review here the structural features, anatomical connectivity and functional properties of the medial and lateral septum. We discuss the heterogeneous anatomy of the lateral septum, which is composed of diverse subregions with distinct ascending and descending projections, and we relate the physiological characteristics of septal nuclei to their functional relationships with the hippocampal formation, the hypothalamus and the brainstem reticular formation during motivated spatial navigation.

Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([d-Lys3]-growth hormone-releasing peptide-6 and JMV-2959) at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the midlight phase, suggesting that pharmacological activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, whereas blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

The role of CA3-LS-VTA loop in the formation of conditioned place preference induced by context-associated reward memory for morphine.

Addiction-related behaviors, such as conditioned place preference (CPP), require animals to remember an association between environmental cue and drug treatment, and exposure to environmental cue is one of the key contributing factors to relapse. However, how central neural circuit participates in the formation of CPP induced by stimulus of morphine-paired environment remains unknown. In the present study, we found that reexposure to morphine-paired environment significantly increased the activity of hippocampal CA3 neurons, increased the excitability of GABAergic neurons and expression of glutamic acid decarboxylase 65/67 in the caudal lateral septum (LSc) and decreased the activity of GABAergic neurons and GAD65/67 expression in ventral tegmental area (VTA), leading to activation (disinhibition) of dopaminergic neurons. Inactivation of CA3 neurons attenuated GABAergic neurons activity and decreased the upregulation of GAD65/67 in LSc, prevented the dopaminergic neurons activation,and GAD65/67 downregulation in VTA and ameliorated the CPP behavior following exposure to morphine-paired context. Blockade of NMDA receptor in LSc also prevented the upregulation of GAD65/67 in LSc and formation of CPP induced by stimulus of morphine-paired environment. Suppression of GAD activity in LSc also remarkably attenuated the dopaminergic neurons activation and the GAD65/67 downregulation in VTA and prevented the formation of CPP induced by reexposure to morphine-associated context. Collectively, these results, for the first time, illustrated the involvement of neural circuitry of CA3-LSc-VTA, through integration of the contexts and reward information, participated in the reinstatement of CPP induced by exposure to morphine-associated context, which advanced our understanding on neurobiological basis for the context-associated memory and rewarding behavior.

Involvement of the oxytocin system in the nucleus accumbens in the regulation of juvenile social novelty-seeking behavior.

Exploration of novel environments, stimuli, and conspecifics is highly adaptive during the juvenile period, as individuals transition from immaturity to adulthood. We recently showed that juvenile rats prefer to interact with a novel individual over a familiar cage mate. However, the neural mechanisms underlying this juvenile social novelty-seeking behavior remain largely unknown. One potential candidate is the oxytocin (OXT) system, given its involvement in various motivated social behaviors. Here, we show that administration of the specific oxytocin receptor antagonist desGly-NH2,d(CH2)5-[Tyr(Me)2,Thr4]OVT reduces social novelty seeking-behavior in juvenile male rats when injected into the nucleus accumbens (10ng/0.5µl/side). The same drug dose was ineffective at altering social novelty-seeking behavior when administered into the lateral septum or basolateral amygdala. These results are the first to suggest the involvement of the OXT system in the nucleus accumbens in the regulation of juvenile social novelty-seeking behavior.

Involvement of lateral septum in alcohol's dopamine-elevating effect in the rat.

Drugs of abuse share the ability to increase extracellular dopamine (DA) levels in the mesolimbic DA system. This effect has been linked to positive and reinforcing experiences of drug consumption and is presumed to be of importance for continued use, as well as for the development of dependence and addiction. Previous rat studies from our lab have implicated a neuronal circuitry involving glycine receptors in nucleus accumbens (nAc) and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area (VTA) in ethanol's (EtOH) DA-elevating effect. The work presented here, performed in male Wistar rats, suggests that the lateral septum (LS), which has previously been associated with different aspects of EtOH-related behaviour, is involved as well. In vivo microdialysis methodology demonstrated that blocking the generation of action potentials in LS using tetrodotoxin prevented a DA increase in nAc after accumbal EtOH perfusion. Retrograde tracing and polymerase chain reaction (PCR) were used to identify and characterize cells projecting to VTA from nAc/LS and from LS to nAc. Based on the PCR results, cells projecting from both LS/nAc to anterior VTA and from LS to nAc were mainly GABAergic neurons expressing glycine receptors, and these cells are presumed to be involved in mediating the DA-elevating effect of EtOH. These results provide further evidence implicating LS in the reinforcing effects of EtOH. Additional studies are needed to investigate LS involvement in EtOH consumption behaviour and its potential role in the development of dependence and addiction.

Effects of pair bonding on dopamine D1 receptors in monogamous male titi monkeys (Callicebus cupreus).

Pair bonding leads to increases in dopamine D1 receptor (D1R) binding in the nucleus accumbens of monogamous prairie voles. In the current study, we hypothesized that there is similar up-regulation of D1R in a monogamous primate, the titi monkey (Callicebus cupreus). Receptor binding of the D1R antagonist [11 C]-SCH23390 was measured in male titi monkeys using PET scans before and after pairing with a female. We found that within-subject analyses of pairing show significant increases in D1R binding in the lateral septum, but not the nucleus accumbens, caudate, putamen, or ventral pallidum. The lateral septum is involved in a number of processes that may contribute to social behavior, including motivation, affect, reward, and reinforcement. This region also plays a role in pair bonding and paternal behavior in voles. Our observations of changes in D1R in the lateral septum, but not the nucleus accumbens, suggest that there may be broadly similar dopaminergic mechanisms underlying pair bonding across mammalian species, but that the specific changes to neural circuitry differ. This study is the first research to demonstrate neuroplasticity of the dopamine system following pair bonding in a non-human primate; however, substantial variability in the response to pairing suggests the utility of further research on the topic.

Melanin-concentrating hormone neurons release glutamate for feedforward inhibition of the lateral septum.

Melanin-concentrating hormone (MCH) regulates vital physiological functions, including energy balance and sleep. MCH cells are thought to be GABAergic, releasing GABA to inhibit downstream targets. However, there is little experimental support for this paradigm. To better understand the synaptic mechanisms of mouse MCH neurons, we performed neuroanatomical mapping and characterization followed by optogenetics to test their functional connectivity at downstream targets. Synaptophysin-mediated projection mapping showed that the lateral septal nucleus (LS) contained the densest accumulation of MCH nerve terminals. We then expressed channel rhodopsin-2 in MCH neurons and photostimulated MCH projections to determine their effect on LS activity. Photostimulation of MCH projections evoked a monosynaptic glutamate release in the LS. Interestingly, this led to a feedforward inhibition that depressed LS firing by a robust secondary GABA release. This study presents a circuit analysis between MCH and LS neurons and confirms their functional connection via monosynaptic and polysynaptic pathways. Our findings indicate that MCH neurons are not exclusively GABAergic and reveal a glutamate-mediated, feedforward mechanism that inhibits LS cells.

Proposed homology of the dorsomedial subdivision and V-shaped layer of the avian hippocampus to Ammon's horn and dentate gyrus, respectively.

The avian hippocampal formation differs considerably from that of mammals both in terms of position and cytoarchitecture. On the basis of fiber connections in pigeons, however, we previously proposed that the dorsomedial subdivision (DM) and the V-shaped layer of the hippocampal formation correspond to Ammon's horn and the dentate gyrus of mammals, respectively. In the present study, we provide evidence in support of this hypothesis by double staining hippocampal neurons using tract-tracing and gene expression. After cholera toxin subunit B (CTB) was injected into the lateral septal nucleus (SL), and vesicular glutamate transporter 2 (vGluT2) mRNA, a gene marker for glutamatergic neurons, was visualized in the same retrogradely labeled neurons with in situ hybridization, most CTB+/vGluT2+ neurons were concentrated in DM, but were rare in the V-shaped layer. The distribution pattern of CTB+/vGluT2+ neurons in the hippocampal formation did not change when CTB injection sites were shifted in a rostrocaudal direction in SL. SL expresses a variety of mRNAs for ionotropic glutamate receptor subunits (GluA1, GluA2, GluK2, GluK4, and GluN1). The findings indicate that DM neurons provide descending glutamatergic axons to SL. Additionally, the present study showed that Prox1 mRNA, a gene marker for the dentate gyrus in mammals, was intensely expressed in the V-shaped layer in the pigeon hippocampus. Together these results strengthen our original hypothesis that DM and the V-shaped layer in the pigeon hippocampus are homologous to Ammon's Horn and the dentate gyrus, respectively. © 2016 Wiley Periodicals, Inc.